Non-Cirrhotic Portal Hypertension: Recognizing the Other Causes

Dr Neeraj Manikath , claude.ai

Abstract

Non-cirrhotic portal hypertension (NCPH) represents a diagnostic challenge that is frequently overlooked in clinical practice. These patients present with classical signs of portal hypertension—variceal bleeding, ascites, or splenomegaly—yet maintain preserved hepatic synthetic function with normal or near-normal liver biochemistry. The failure to recognize NCPH leads to misdiagnosis, inappropriate management, and missed opportunities for specific therapeutic interventions. This review provides a comprehensive framework for understanding, diagnosing, and managing NCPH, with practical pearls for the internist.

Introduction

Portal hypertension is traditionally synonymous with cirrhosis in the minds of most clinicians. However, 5-10% of patients with portal hypertension have non-cirrhotic causes, and in certain geographic regions (particularly where schistosomiasis is endemic), this proportion is substantially higher.¹ The critical distinguishing feature of NCPH is the preservation of hepatic synthetic function—normal albumin, bilirubin, and coagulation parameters—despite obvious signs of portal hypertension. This preservation occurs because the hepatocyte mass remains largely intact, even when portal blood flow is severely compromised.

Pearl #1: When you encounter a patient with varices or splenomegaly but normal albumin and liver function tests, immediately expand your differential beyond cirrhosis. The liver synthetic function is your compass.

Anatomical Framework: Pre-Sinusoidal, Sinusoidal, and Post-Sinusoidal

Understanding NCPH requires anatomical thinking. Portal hypertension develops when resistance to portal blood flow increases at any point from the portal vein to the hepatic veins and right atrium. The classification system based on the site of obstruction provides both diagnostic and therapeutic clarity.

Pre-Sinusoidal Causes

Portal Vein Thrombosis (PVT)

PVT is the most common pre-sinusoidal cause of NCPH globally.² Acute PVT may present with abdominal pain, but chronic PVT typically manifests insidiously with variceal bleeding or splenomegaly. The formation of portoportal collaterals (cavernous transformation) is a hallmark of chronic disease.

Etiology: The underlying causes include inherited thrombophilias (Factor V Leiden, prothrombin G20210A mutation, protein C/S deficiency), myeloproliferative neoplasms (particularly JAK2-positive disorders), paroxysmal nocturnal hemoglobinuria, antiphospholipid syndrome, local factors (pancreatitis, abdominal sepsis, surgical trauma), and neonatal umbilical sepsis (presenting years later).³

Oyster #1: Always screen for JAK2 V617F mutation in unexplained PVT, even without overt hematologic abnormalities. Up to 40% of non-cirrhotic, non-malignant PVT cases harbor myeloproliferative neoplasms.⁴

Schistosomiasis

In endemic areas (sub-Saharan Africa, Egypt, Brazil, parts of Asia), Schistosoma mansoni and S. japonicum cause periportal fibrosis (Symmers' pipestem fibrosis) through granulomatous reaction to deposited eggs in portal venules. This creates pre-sinusoidal obstruction with massive splenomegaly and preserved liver function—the classic "big spleen, good liver" scenario.⁵

Sarcoidosis

Hepatic sarcoidosis causes portal hypertension through granulomatous infiltration of portal tracts, leading to presinusoidal obstruction. It accounts for less than 1% of NCPH cases but is important because it's treatable. Look for systemic features—hilar lymphadenopathy, uveitis, elevated ACE levels—though isolated hepatic involvement occurs.⁶

Pearl #2: In patients from endemic regions presenting with portal hypertension and normal liver function, obtain serological testing and rectal biopsy for schistosomiasis before pursuing more invasive investigations.

Sinusoidal Causes

Nodular Regenerative Hyperplasia (NRH)

NRH is characterized by diffuse micronodular transformation of the liver without fibrous septa—a key pathologic distinction from cirrhosis. The nodules represent hepatocyte hyperplasia with atrophy of intervening parenchyma, causing sinusoidal compression and portal hypertension.

Associations: NRH has strong links with autoimmune diseases (rheumatoid arthritis, systemic sclerosis, ANCA-associated vasculitis), immunosuppressive medications (azathioprine, 6-mercaptopurine), chemotherapeutic agents (oxaliplatin), and HIV infection.⁷ The exact pathophysiology remains debated but likely involves obliterative portal venopathy and microvascular injury.

Diagnostic Challenge: NRH is notoriously difficult to diagnose. Standard needle biopsy may miss the diagnosis because nodules are small and uniformly distributed. Reticulin staining is essential, showing nodular hepatocyte plates without surrounding fibrosis.⁸

Hack #1: If clinical suspicion for NRH is high but initial biopsy is unrevealing, consider repeat biopsy with specific instructions to the pathologist for reticulin staining and multiple cores. Cross-sectional imaging (CT/MRI) typically shows heterogeneous liver perfusion but is non-specific.

Infiltrative Diseases

Hepatic amyloidosis, while rare, can cause sinusoidal deposition of amyloid fibrils, increasing intrahepatic resistance. Patients typically have systemic amyloidosis with cardiac, renal, or neurologic involvement. Hepatomegaly is common, and elevated alkaline phosphatase is more typical than transaminase elevation.⁹

Post-Sinusoidal Causes

Budd-Chiari Syndrome (BCS)

BCS results from hepatic venous outflow obstruction, most commonly due to thrombosis of hepatic veins, though IVC obstruction and webs also occur. The presentation varies from acute fulminant hepatic failure to chronic insidious portal hypertension.

Classic Triad: Abdominal pain, ascites, and hepatomegaly. However, many patients present with only one or two features. Ascites in BCS is characteristically high-protein (serum-ascites albumin gradient >1.1g/dL but total protein >2.5g/dL), unlike cirrhotic ascites.¹⁰

Underlying Causes: Similar to PVT—myeloproliferative neoplasms are found in 40-50% of cases in Western populations. Other causes include inherited thrombophilias, oral contraceptives, pregnancy, Behçet's disease, and paroxysmal nocturnal hemoglobinuria.¹¹

Pearl #3: The combination of acute hepatitis picture (elevated transaminases) with ascites and hepatomegaly should trigger immediate Doppler ultrasound to evaluate hepatic vein patency. Early recognition and anticoagulation can be liver-saving.

Cardiac Causes

Right-sided heart failure and constrictive pericarditis cause hepatic congestion and sinusoidal dilatation, resulting in "congestive hepatopathy." Chronic congestion can lead to cardiac cirrhosis, but earlier stages present as NCPH with preserved synthetic function.

Diagnostic Clues: Elevated jugular venous pressure, peripheral edema, pulsatile hepatomegaly, and ascites with very high SAAG (>2.0 g/dL). Echocardiography reveals right ventricular dysfunction or constrictive physiology. Cardiac MRI is gold standard for constrictive pericarditis diagnosis.¹²

Oyster #2: In patients with "cryptogenic cirrhosis" and ascites, always examine the neck veins and consider cardiac imaging. Constrictive pericarditis is the great masquerader and potentially curable with pericardiectomy.

Diagnostic Pathway: A Systematic Approach

The diagnosis of NCPH requires high clinical suspicion and systematic investigation.

Step 1: Recognize the Clinical Pattern

Portal hypertension manifestations (variceal bleeding, ascites, splenomegaly, thrombocytopenia from hypersplenism) PLUS preserved liver synthetic function (normal albumin, bilirubin, INR). This discordance should trigger the NCPH diagnostic pathway.

Hack #2: Calculate the MELD score. In true NCPH, MELD scores are typically <10-12, despite significant portal hypertension. A patient with varices and MELD of 8 almost certainly has NCPH rather than cirrhosis.

Step 2: Vascular Imaging with Doppler Ultrasound

First-line investigation should be Doppler ultrasound to assess:

Portal vein patency and flow direction (hepatopetal vs hepatofugal)
Hepatic vein patency and phasicity
Cavernous transformation (PVT)
Splenomegaly and splenic vein patency

Doppler has 80-90% sensitivity for PVT and >85% for BCS, though operator dependency is significant.¹³

Step 3: Cross-Sectional Imaging

CT or MRI with venous phase provides superior anatomic detail and can identify:

Hepatic vein thrombosis or IVC webs
Portosystemic collaterals
Liver morphology (nodularity suggesting NRH)
Periportal thickening (schistosomiasis)
Mesenteric or splenic vein thrombosis

Pearl #4: MRI with hepatobiliary contrast agents can reveal the subcapsular hyperenhancement ("flip-flop" sign) characteristic of Budd-Chiari syndrome.

Step 4: Evaluate for Underlying Etiologies

Thrombophilia workup: Factor V Leiden, prothrombin G20210A, protein C/S, antithrombin III, antiphospholipid antibodies, JAK2 V617F mutation, paroxysmal nocturnal hemoglobinuria (flow cytometry for CD55/CD59-deficient cells).

Autoimmune markers: ANA, anti-dsDNA, RF, anti-CCP, ANCA for associations with NRH.

Infectious: Schistosomal serology, stool and rectal biopsy in endemic regions.

Cardiac evaluation: Echocardiography, BNP, and cardiac MRI if indicated.

Step 5: Consider Liver Biopsy

Transjugular liver biopsy (TJLB) is preferred over percutaneous biopsy in NCPH because:

Portal hypertension increases bleeding risk
Allows measurement of hepatic venous pressure gradient (HVPG)
Can perform hepatic venography

Histologic Patterns:

NRH: Nodules without fibrosis on reticulin stain
Schistosomiasis: Periportal fibrosis with granulomas
Incomplete septal cirrhosis: Thin fibrous septa not encircling nodules
Portal venopathy: Portal tract abnormalities without cirrhosis

Hack #3: Measure HVPG during TJLB. In pre-sinusoidal NCPH (PVT, schistosomiasis), HVPG is typically normal or mildly elevated (<10 mmHg), whereas in sinusoidal/post-sinusoidal causes and cirrhosis, HVPG is significantly elevated (≥10 mmHg). This measurement provides important prognostic information.¹⁴

Management Strategies

Management of NCPH requires addressing both the underlying etiology and the complications of portal hypertension.

Treating the Underlying Cause

Anticoagulation: For PVT and BCS, anticoagulation is cornerstone therapy. Early initiation improves recanalization rates and prevents extension. Low molecular weight heparin transitioned to warfarin or direct oral anticoagulants is standard, though DOACs have limited data in this setting. Duration is typically lifelong if underlying thrombophilia exists.¹⁵

Immunosuppression: For sarcoidosis-related NCPH and associated autoimmune conditions in NRH, corticosteroids may reduce portal tract inflammation and improve portal hemodynamics.

Antiparasitic therapy: Praziquantel for schistosomiasis prevents disease progression but does not reverse established fibrosis.

Cardiac intervention: Pericardiectomy for constrictive pericarditis, heart failure optimization, or valve replacement as indicated.

Managing Portal Hypertension Complications

Variceal Management: Identical to cirrhotic portal hypertension:

Acute bleeding: Vasoactive drugs (octreotide, terlipressin) plus endoscopic band ligation
Secondary prophylaxis: Non-selective beta-blockers (propranolol, carvedilol) plus repeat banding until eradication
Primary prophylaxis: Beta-blockers if large varices present¹⁶

Oyster #3: NCPH patients often tolerate variceal bleeding better than cirrhotics due to preserved liver function, but don't become complacent—exsanguination is still possible.

Ascites Management: Sodium restriction and diuretics (spironolactone plus furosemide) following the same principles as cirrhotic ascites. However, NCPH ascites may be more refractory because portal hypertension is often more severe relative to liver dysfunction.

Pearl #5: In BCS, ascites tends to be more responsive to diuretics once anticoagulation is established and partial recanalization occurs.

Hypersplenism: Usually doesn't require intervention unless severe thrombocytopenia causes bleeding. Splenectomy or splenic artery embolization are options but should be reserved for refractory cases given infectious risks.

Advanced Therapies

Transjugular Intrahepatic Portosystemic Shunt (TIPS): TIPS can be considered for refractory variceal bleeding or ascites in NCPH. Outcomes are generally excellent given preserved liver function, with lower rates of post-TIPS hepatic encephalopathy compared to cirrhosis.¹⁷

Liver Transplantation: Rarely needed in NCPH unless underlying disease progresses (BCS with hepatocyte necrosis, progression to cirrhosis). However, transplantation addresses both the portal hypertension and removes the thrombogenic liver in BCS, potentially allowing cessation of anticoagulation.

Prognosis

Prognosis in NCPH is significantly better than cirrhotic portal hypertension, primarily because hepatic synthetic function remains preserved. Five-year survival exceeds 85% in most series, compared to 50-60% for decompensated cirrhosis.¹⁸ However, outcomes depend heavily on etiology and successful management of the underlying condition.

Prognostic Factors:

Extent of portal vein thrombosis (complete vs partial)
Presence of portosystemic shunts (spontaneous decompression)
Response to anticoagulation in thrombotic causes
Development of portal cholangiopathy (ischemic bile duct injury from chronic PVT)

Conclusion

Non-cirrhotic portal hypertension is an under-recognized entity that demands clinical vigilance. The combination of portal hypertension with preserved liver synthetic function should immediately broaden the differential diagnosis beyond cirrhosis. A systematic anatomical approach—pre-sinusoidal, sinusoidal, post-sinusoidal—guides investigation and management. Doppler ultrasound is the critical first imaging test, followed by targeted workup for thrombophilia, autoimmune disease, and cardiac pathology. Unlike cirrhosis, many causes of NCPH are treatable, making accurate diagnosis essential. The preserved liver function confers better prognosis but doesn't eliminate the risks of variceal hemorrhage and other complications requiring aggressive management.

References

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Final Pearl: When in doubt, remember that the liver is remarkably honest. If it's making adequate albumin and maintaining normal coagulation, the hepatocytes are functioning well regardless of portal pressures. Let this guide your diagnostic thinking toward non-cirrhotic causes.

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