Noncirrhotic Portal Hypertension and Pathology of the Sinusoids. Ian R. Wanless Department of Pathology Dalhousie University Halifax, Canada

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1 Noncirrhotic Portal Hypertension and Pathology of the Sinusoids Ian R. Wanless Department of Pathology Dalhousie University Halifax, Canada

2 Non cirrhotic portal hypertension Extrahepatic portal vein obstruction Intrahepatic (microvascular) obstruction Idiopathic portal hypertension (Japan) Non cirrhotic portal fibrosis (India) Hepatoportal sclerosis (USA)

3 Non cirrhotic portal hypertension Extrahepatic portal vein obstruction Thrombosis, congenital malformation Intrahepatic (microvascular) obstruction Idiopathic portal hypertension (Japan) Non cirrhotic portal fibrosis (India) Hepatoportal sclerosis (USA) Portal tract inflammation

4 Schistosomiasis

5 Schistosomiasis

6 Primary biliary cirrhosis

7 Polyarteritis nodosa Ménage à foie: injury to adjacent portal tract structures Wanless IR: Understanding non-cirrhotic portal hypertension. Hepatology 1988.

8 These classical descriptions of NCPH are incomplete: Parenchymal and hepatic vein changes are frequently seen. schistosomiasis

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12 Idiopathic portal hypertension from Professor M. Kage, Japan

13 Idiopathic portal hypertension from Professor M. Kage, Japan

14 Non cirrhotic portal fibrosis from Professor P. Sakhuja, India

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18 These lesions are reminiscent of regressing cirrhosis

19 Regression of HBV cirrhosis with lamivudine 2.5 years later Wanless et al. Arch Pathol Lab Med 2000

20 Micro to macronodular regression

21 Incomplete septal cirrhosis

22 Delicate septa in cirrhosis 224

23 Portal tract remnants PV loss, identical to NCPH

24 To understand non cirrhotic portal hypertension we need to understand cirrhosis.

25 Cirrhosis: A lesion composed of nodules, separated by parenchymal extinction ( fibrous septa ) Parenchymal extinction: Loss of contiguous hepatocytes

26 You can see parenchymal extinction grossly as collapse. 1500g <1000g

27 Under the microscope, you can see small Parenchymal extinction lesions (PELs): Collapse with approximation of portal tracts and hepatic veins

28 Parenchymal extinction lesions (PELs) in chronic hepatitis B

29 Glutamine synthetase Chronic Hepatitis C (F1 2) Small PELs

30 Parenchymal extinction lesions are early events in chronic liver disease. What is the mechanism?

31 Vascular obstruction, especially of hepatic veins: Thrombosis, as in Budd Chiari Syndrome Inflammation, as in chronic hepatitis

32 Chronic hepatitis B

33 Alcoholic hepatitis

34 Aggregation of PELs: Small collapse lesions are converted to septa. hepatitis C

35 PELs (septa) occur where obstructed HVs are located.

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37 Distribution of hepatic vein obstruction: (chronic hepatitis) Stage 1 2 Stage 4A Stage 4C Explained by the Congestive Escalator

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41 Summary NCPH caused by Portal vein thrombosis, congenital anomalies Portal tract inflammation Schistosomiasis, arteritis, etc Any parenchymal injury Low activity, so that congestive escalator is avoided OR Long recovery time, allowing recruitment of collateral drainage, regeneration (repopulation of septa) and resorption of any fibrosis.

42 Kawasami Dr. Masayuki Nakano, National Mito Hospital

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44 Summary Lesions heal nearly completely, unless there is a relatively irreversible component, such as: Continued inflammation (production of new lesions) Portal tract conversion (driven by tissue pressure and angiogenesis) Congestive escalator (driven by tissue pressure) Septa are an indication that parenchymal injury has occurred (with PELs) After septa regress, there remain obliterated PVs and HVs, as seen in NCPH.

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46 Summary: Driving forces in chronic liver disease. Local intrahepatic pressure gradients cause parenchymal and vascular injury. These gradients can be understood in terms of blood flows: In out imbalance These gradients drive two main processes that explain the tissue lesions. 1. Portal tract conversion (arterialization) 2. The congestive escalator Inflammation induces most chronic liver disease Fibrosis is not a central feature in chronic liver disease.

47 Natural history of obstructed veins OPV remains portal tract conversion OHV may remain (but are resorbed or obscure) may extend ( congestive escalator )

48 Conclusions Many cases of IPH and NCPF are histologically the same as regressing cirrhosis or incomplete cirrhosis seen in North America.

49 Conclusions NCPF is histologically the same as regressing cirrhosis or incomplete cirrhosis seen in North America. NCPF is a collection of diseases with dominant PV obstruction Thrombosis Local portal tract inflammation Any chronic liver disease (in which primary disease is inactive and regressed)

50 Summary Most anatomic forms of chronic liver disease can be described in terms of the distribution of venous obstruction.

51 Summary Most anatomic forms of chronic liver disease can be described in terms of the distribution of venous obstruction. Portal vein obstruction is irreversible ( portal tract conversion )

52 Summary Most anatomic forms of chronic liver disease can be described in terms of the distribution of venous obstruction. Portal vein obstruction is irreversible ( portal tract conversion ) Hepatic vein obstruction may remain or extend ( congestive escalator )

53 Summary Most anatomic forms of chronic liver disease can be described in terms of the distribution of venous obstruction. Portal vein obstruction is irreversible ( portal tract conversion ) Hepatic vein obstruction may remain or extend ( congestive escalator ) The hepatic vein is the Achilles heel of the liver.

54 Angiopoietin 1 effect in liver Ward N, et al. Am J Pathol 2004 Angiopoietin 1 was expressed in hepatocytes in transgenic mice. During expression: arterial enlargement and sprouting loss of small portal veins After turning off expression: Portal veins returned

55 Wild type Double transgenic Double transgenic with angiopoietin-1 gene suppressed for 14 days Arterialization may prevent development of portal veins by arterial pressure in the sinusoids.

56 Portal tract inflammation Parenchymal necro-inflammation congestive escalator OPV large OPV small (portal tract conversion) sinusoidal injury Parenchymal extinction OHV small OHV medium retrograde congestion OHV large

57 Portal vein thrombosis toxic or ischemic injury infection e.g. virus alcohol NASH Hepatic vein thrombosis Portal tract inflammation Parenchymal necro-inflammation congestive escalator OPV large OPV small (portal tract conversion) sinusoidal injury Parenchymal extinction OHV small OHV medium retrograde congestion OHV large

58 Retrograde congestion

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60 Fibrosis is transient in animal models Gastroenterology 2012

61 Regression of cirrhosis 1. Enlargement of existing nodules Wanless et al, 2000

62 Regression of cirrhosis 1. Enlargement of existing nodules 2. Formation of new nodules: Buds Updated in Stueck and Wanless, Hepatology, In press.

63 Buds Wanless et al, 2000