•PORTAL HYPERTENSION :Pathophysiology {molecular mechanism}

and Classification

Dr. Gnanendra DMPostgraduate trainee,

Dept of Gastroenterology.

• As early as the 17th century, it was realized that structural changes in the portal circulation could cause gastrointestinal bleeding.

• In 1902, Gilbert and Carnot introduced the term "portal hypertension" to describe this condition.

Introduction of Portal Hypertension

Then, What's Portal Hypertension?

Definition

• Portal hypertension is defined by a pathologic increase in portal pressure, in which the pressure gradient between the portal vein and inferior vena cava (the portal pressure gradient (PPG)) is increased above the upper normal limit of 5 mmHg.

• PPG values between 6 and 10mmHg represent subclinical portal hypertension

• Portal hypertension becomes clinically significant when the PPG increases above the threshold value of

• >10mmHg ( formation of varices) • >12mmHg ( variceal bleeding, ascites)

• This increased pressure results from a functional obstruction to blood flow from any point in the portal system's origin (in the splanchnic bed) through the hepatic veins (exit into the systemic circulation) or from an increase in blood flow in the system.

Anatomy of Portal System

The portal vein supplies 70% of the blood flow to the liver, but only 40% of the liver oxygen supply. The remainder of the blood comes from the hepatic artery, and blood from both of these vessels mixes in the sinusoids.

Venous anatomy of gastroesophageal junction

The intrinsic veins of the gastroesophageal junction are divided into four well-defined zones.

• 1 Gastric zone: 2–3 cm zone with its upper border at the gastroesophageal junction and is composed of a radial band of veins in the submucosa and lamina propria.

• 2 Palisade zone: commences at the gastroesophageal junction and extends cranially for 2–3 cm and is a direct extension of the veins of the gastric zone, which run in “palisades” or packs of longitudinally arrayed veins in the lamina propria. These veins are the primary site of communication between the portal bed and azygous bed.

• 3 Perforating zone: the intrinsic veins drain into the extrinsic veins primarily in this region via valved per-forating veins.

• 4 Truncal zone: an 8–10 cm zone extending upward from the perforating zone.

• Flow direction in these veins is from a cranial to caudal direction and drains via the perforating veins into the extrinsic veins.

• In cases of portal hypertension, an adaptive increase in flow through the portasystemic communications occurs to return blood to the heart.

• The vessels involved, especially the intrinsic veins around the gastroesophageal(GE) junction dilate and become tortuous forming varicose veins.

• The pathophysiologic process of portal hypertension consists of three components: intrahepatic circulation, systemic (splanchnic) circulation, and collateral circulation.

• Additionally, continuous abnormalities in systemic circulation induce hyperdynamic circulation.

Guturu P, Shah V. New insights into the pathophysiology of portal hypertension. Hepatol Res 2009;39:1016-1019

PathogenesisThe portal vein carries approximately 1500 mL/min of blood from the small and large bowel, the spleen, and the stomach to the liver.

Obstruction of portal venous flow, whatever the etiology, results in a rise in portal venous pressure.

The response to increased venous pressure is the development of collateral circulation that diverts the obstructed blood flow to the systemic veins.

These portosystemic collaterals form by the opening and dilatation of preexisting vascular channels connecting the portal venous system and the superior and inferior vena cava.

• Development of portal hypertension can be influenced by changes in resistance and flow in the hepatic vasculature.

• Increased resistance of portal blood flow in cirrhotic liver induces portal venous dilatation and congestion of portal venous flow, leading to elevated portal pressure. Subsequently, portosystemic collaterals develop to counterbalance the increased resistance in portal blood flow, and induce an increase in venous return to heart which results in increased portal venous inflow. This hyperdynamic splanchnic circulation contributes to the maintaince and aggravation of portal hypertension

Ohm law is P = F R, (pressure= flow×resistance).

Increase in vascular resistance The initial factor in the etiology of portal hypertension is the increase in vascular resistance to the portal blood flow.

Poiseuille’s law, which can be applied to portal vascular resistance, R, states that R = 8hL/pr4, where h is the viscosity of blood, L is the length of the blood vessel, and r is the radius of the blood vessel.

The viscosity of the blood is related to the hematocrit. The lengths of the blood vessels in the portal vasculature are relatively constant.

Thus, changes in portal vascular resistance are determined primarily by blood vessel radius.

Because portal vascular resistance is indirectly proportional to the fourth power of the vessel radius, small decreases in the vessel radius cause large increases in portal vascular resistance and, therefore, in portal blood pressure (P = F8hL/pr4, where P is portal pressure and F is portal blood flow).

Liver disease that decreases the portal vascular radius produces a dramatic increase in portal vascular resistance. In cirrhosis, the increase occurs at the hepatic microcirculation (sinusoidal portal hypertension).

Increased hepatic vascular resistance in cirrhosis is not only a mechanical consequence of the hepatic architectural disorder; a dynamic component also exists due to the active contraction of myofibroblasts, activated stellate cells, and vascular smooth-muscle cells of the intrahepatic veins.

Endogenous factors and pharmacologic agents that modify the dynamic component include those that increase or decrease hepatic vascular resistance.

Factors that increase hepatic vascular resistance include endothelin-1 (ET-1), alpha-adrenergic stimulus, and angiotensin II.

Factors that decrease hepatic vascular resistance include nitric oxide (NO), prostacyclin, and vasodilating drugs (eg, organic nitrates, adrenolytics, calcium channel blockers).

1 Intra hepatic circulation

• Vasoregulatory imbalances and increased intrahepatic resistance

• Sinusoidal Remodeling and Angiogenesis

Vasoregulatory imbalances and increased intrahepatic resistanceHepatic stellate cells (HSCs) play a central role in producing dynamic components of intra hepatic resistance by causing sinusoidal vasoconstriction through “contractile machinery” and relaxation in response to the interaction between sinusoidal endothelial cells (SECs) and HSCs; their paracrine effects are accomplished through endothelin-1 (ET-1) and nitric oxide (NO). Normally, ET-1 is secreted from SECs and acts on ETA receptors on HSCs leading to HSC contraction. Conversely, NO released from SECs by endothelial NO synthase (eNOS) induces relaxation of HSCs through the guanylate catalase pathway. Consequently, the balance between the ET-1 and NO accounts for the control of sinusoidal flow.

Intra hepatic circulation

• in cirrhotic liver, the overproduction of ET-1 and increased susceptibility to autocrine ET-1 leading to activated HSCs result in increasing HSC contraction. In addition, multiple derangements in eNOS derived NO generation by SECs contribute to impaired sinusoidal relaxation and increased intrahepatic resistance (endothelial dysfunction). SECs show a prominent increase in the inhibitory protein caveolin binding to eNOS with concomitant decreased calmodulin binding, which may contribute to NOS dysfunction.

Recent studies have shown impaired phosphorylation and activation of eNOS mediated through alterations in G-protein coupled receptor signaling and defects in endogenous inhibitors of NOS, which suggest that multiple molecular defects likely contribute to a significant deficiency in hepatic NO production during cirrhosis.

Animal experiments have demonstrated that activation of hepatic eNOS can improve portal hemodynamics in cirrhotic rat liver.

Langer DA, Shah VH. Nitric oxide and portal hypertension: interface of vasoreactivity and angiogenesis. J Hepatol 2006;44:209-216.

Recent study evaluated the effects of simvastatin on intrahepatic vascular tone acting as an eNOS activator in humans.

Patients who received simvastatin showed increased hepatic venous NO products and decreased hepatic vascular resistance without untoward systemic vascular effects.

Fernandez M et al, Gastroenterology 2009;126:749-755.

Sinusoidal Remodeling and Angiogenesis

HSC density and coverage of the sinusoidal lumen are increased in cirrhosis. The contractile nature and long cytoplasmic processes of HSCs encircling endothelial cells induce sinusoidal vessel constriction with increased vascular resistance termed “sinusoidal vascular remodeling”.

The characteristics of sinusoidal remodeling are distinct from process of fibrosis, collagen deposition of HSC. In this process, HSC motility and migration is absolutely required to promote enhanced coverage of HSCs around a SECs-lined sinusoid.

Straub AC et al . sinusoidal endothelial cell capillarization and vessel remodeling in mouse liver. Hepatology 2007;45:205-212

While Transforming growth factor-β (TGF-β) is largely recognized for its contribution to HSC-based collagen deposition, there is significant crosstalk between TGF-β and PDGF involved in HSCs motility. Indeed, these signals may converge at the level of c-abl tyrosine kinase. A number of signaling pathways mediate HSC recruitment to vessels in vascular remodeling and angiogenesis including PDGF, TGF-β, angiopoietins, and NO. Platelet derived growth factor (PDGF) is probably the most critical factor in the recruitment of pericytes to newly formed vessels.SECs also undergo substantive phenotypic changes in cirrhosis that likely contribute to changes in sinusoidal structure. Indeed, recent studies have identified a number of alterations in SEC phenotypes

Ceni E,et al : Gastroenterology 2006;131: 1235-1252

• Peptide hormone Relaxin RXFP1receptor

Activates intra hepatic NO signaling Decrease the activaion and fibrinogenic phenotype of HSC.

Relaxin treatment reduces poratl pressure without systemic hypotension

Fernandez Hepatology, vol 61, no 4 , april 2015

Eicosanoids

Thromboxane A2

Cox Prostaglandin H2 LTc4

Lox LTd4

LTe4

Inhibition of leukotriene receptor(montelukast) reduces portal perfusion pressure.

Fernandez Hepatology, vol 61, no 4 , 2015

• Vasoconstrictor• Fibrogenesis• angiogenesis

• Nago –B belongs to family reticulon proteins.• It promotes liver fibrosis by facilitating TGF-

beta signaling pathway induces antiapoptotic effects on HSCs

• Selective blockade of Nago-B in HSC represent therapeutic strategy to mitigate liver fibrosis.

Tashiro K et al, Am J pathol 2013:182;786-795

Micro RNAs• They act as fine tuning regulators of HSC and Enothelial cell

functions• Their dysregulation have a role in liver fibrogenesis and

angiogenesis• Micro RNAs ,Which inhibits proteins involved in activation of

HSC in down regulated liver fibosis• Inhibits expression of aquaporin-1, that promotes angiogenesis,

fibrosis , PHT in cirrhotic liver.

• Lakner AM et al. inhibitory effect of micro RNA19b in HSC mediated fibrogenesis. Hepatology 2013;56:300-310

Systemic and splanchnic circulation

• Vasoregulatory imbalances in the splanchnic circulation

• Vascular remodeling of systemic vessels in portal hypertension

Molecular pathways associated to splanchnic vasodilation

Martell M et al . Splanchnic vasodilation in portal hypertensionWorld J Hepatol 2010 June 27; 2(6): 208-220

Vasoregulatory imbalances in the splanchnic circulation

In contrast to diminished intrahepatic bioavailability of NO, splanchnic (and systemic) circulation shows a relative excess inregional NO generation.This increased production is largely endothelium-dependent, and is thought to be evidence of eNOS activation in splanchnic endothelium. Some studies have shown that eNOS activation by the angiogenic growth factor, vascular endothelial growth factor (VEGF), may be a primary factor in initial eNOS activation which demonstrates interesting links between vasodilating, angiogenesis and vascular remodeling.

Wiest R, et al, J Clin Invest 1999;104:1223-1233

Bacterial translocation during cirrhosis increases tumor necrosis factor-α (TNF-α) production which can also induce the increase of systemic NO production.Therefore, increased NO production in systemic and splanchnic circulation contributes to decreased systemic vascular resistance and resultant hyperdynamic circulation. This in turn results in sodium retension and ascites mediated by a reduction of effective circulating volume, stimulation of sympathetic system, an activation of the renin-angiotensin-aldosteron system, and an increase of antidiuretic hormone release

Rudic RD,et al : Direct evidence for the importance of endothelium-derived nitric oxide vascular remodeling. J Clin Invest 1998;101:731-736

Vascular remodeling of systemic vessels in portalhypertension

Vascular remodeling is a long-term adaptive response to chronic changes in blood flow. Chronic increases in flow with dilation of the vascular channel are implicated in endothelial-based signals that mediate restructuring of the vessel, thereby allowing for chronic increases in vessel diameter and capacity for high volume flow. This change has been demonstrated in peripheral vessels including experimental models of portal hypertension which may be related to activation of eNOS.

3.Collateral circulation

• Vasoregulatory imbalances in collateral circulation

• Angiogenesis and vascular remodeling in collateral circulation

Four ramus communicans betweenportal and systemic circulations

esophageal and gastric veins

inferior rectal-anal veins

anterior abdominal wall veins retroperitoneal venous plexus

Vasoregulatory imbalances in collateral circulation

The development of portosystemic shunts and collateral circulation such as esophageal and hemorrhoidal collateral vessels is a compensatory response to decompress the portal circulation and hypertension, but unfortunately contributes to significant morbidity and mortality. Vasodilation of pre-existing collateral vessels results in increased collateral blood flow and volume. The control of collateral circulation could be a key in managing complications of portal hypertension, therefore, experimental studies are performed.

The Korean Journal of Hepatology Vol. 16. No. 4, December 2010

Angiogenesis and vascular remodeling in collateralcirculation

In addition to vasodilatation, the collateral circulatory bed develops through angiogenesis.

Angiogenesis occurs through the proliferation of endothelial and smooth muscle cells in addition to vasculogenesis.

Vasculogenesis refers to the recruitment of endothelial progenitor cells for the de novo synthesis of vessels. Angiogenesis and vasculogenesis are also influenced by NO and highly dependent on VEGF as the growth factor exerting pleiotropic effects to promote new vessel formation.

VEGF promotes vasodilation, vascular remodeling, and angiogenesisin part through NO-dependent or independent mechanisms.

Multikinase inhibitors such as sorafenib by blocking VEGF receptor result in decreases of portosystemic shunts and improvement of portal hypertension but also inactivation of HSCs.

Fernandez M. et al, Beneficial effects of sorafenib on splanchnic, intrahepatic, and portocollateral circulations in portal hypertensive and cirrhotic rats. Hepatology 2009;49:1245-1256.

• Placental Growth Factor(PLGF) : it is another member of VEGF family

• Antagonization of PLGF receptor is a good target for therapy with less sever side effects than the blockade of VEGF

• Vasohibin -1 : recently identified endogenous inhibitor of angiogenesis by VEGF- vasohibin negative – feed back loop

• Vasohibin-1 might be a novel and promising therapeutic strategy for halting

Chronic liver disease progression. Fernandez Hepatology, vol 61, no 4 , april 2015.

Formation of varicesAn elevated pressure difference between systemic and portal circulation (ie, HVPG) directly contributes to the development of varices.HVPG is a surrogate marker of portal pressure gradient and is derived from WHVP corrected (subtracted) with free hepatic venous pressure (FHVP).The hypertensive portal vein is decompressed by diverting up to 90% of the portal flow through portasystemic collaterals back to the heart, resulting in enlargement of these vessels. These vessels are commonly located at the gastroesophageal junction, where they lie subjacent to the mucosa and present as gastric and esophageal varices.

Varices form when the HVPG exceeds 10 mm Hg; they usually do not bleed unless the HVPG exceeds 12 mm Hg (normal HVPG: 1-5 mm Hg). Gastroesophageal varices have 2 main inflows. The first is the left gastric or coronary vein, and the second is the splenic hilum, through the short gastric veins. The gastroesophageal varices are important because of their propensity to bleed. 

Normal venous flow through the portal and systemic circulation. IMC = inferior mesenteric vein; IVC = inferior vena cava; SVC = superior vena cav

Redirection of flow through the left gastric vein secondary to portal hypertension or portal venous occlusion. Uphill varices develop in the distal one third of the esophagus. IMC = inferior mesenteric vein; IVC = inferior vena cava; SVC = superior vena cava.

Grading of esophageal varices

• Esophageal varices are often graded by size • F1: small, straight varices.• F2: enlarged, tortuous varices, occupying less

than one third of the lumen.• F3: large, coil-shaped varices, occupying more

than one third of the lumen.

Grading of Gastric varices• Gastric varices are classified by location

• type 1 : along the lesser curve.• type 2: along the greater curve extending towards the

fundus of the stomach. Isolated gastric varices:

• type 1: isolated cluster of varices in the fundus of the stomach.

• type 2 : isolated gastric varices in other parts of the stomach.

Mechanisms of variceal hemorrhage

Increased portal pressure contributes to increased varix size and decreased varix wall thickness, thus leading to increased variceal wall tension. Rupture occurs when the wall tension exceeds the elastic limits of the variceal wall. Varices are most superficial at the gastroesophageal junction and have the thinnest wall in that region; thus, variceal hemorrhage invariably occurs in that area

The following are risk factors for variceal hemorrhage :Variceal size - The larger the varix, the higher the risk of rupture and bleeding; however, patients may bleed from small varices tooThe presence of endoscopic red color signs (eg, red wale markings, cherry red spots)Child B or C classification, especially the presence of ascites, increases the risk of hemorrhageActive alcohol intake in patients with chronic, alcohol-related liver diseasesLocal changes in the distal esophagus (eg, gastroesophageal reflux) – These have been postulated to increase the risk of variceal hemorrhage.Bacterial infection - A well-documented association exists between variceal hemorrhage and bacterial infections, and this may represent a causal relationship

Note that bacterial infection could also trigger variceal bleeding through a number of mechanisms, including the following:• The release of endotoxin into the systemic circulation• Worsening of hemostasis• Vasoconstriction induced by the contraction of stellate cells

Goulis J, et al. Bacterial infection is independently associated with failure to control bleeding in cirrhotic patients with gastrointestinal hemorrhage. Hepatology 1998;27:1207-1212

4.Hyperdynamic circulation

The hyperdynamic circulation is characterized by increased cardiac output and heart rate, and decreased systemic vascularresistance with low arterial blood pressure in cirrhotic patients. These hemodynamic alterations are initiated by systemic and splanchnic vasodilatation, and eventually lead to abnormalities of the cardiovascular system and several regionalvascular beds including ones involved in hepatic, splanchnic, renal, pulmonary, skeletal muscle and cerebral circulation.

Pathogenesis of hyperdynamic circulation in cirrhosis and portal hypertension.

Multi-organ involvement

gut and liver receive a third of the entire cardiac output, hyperdynamic circulation directly or indirectly contributes to two of the most troublesome complications of cirrhosis: ascites and variceal bleeding

Heart

Cirrhotic cardiomyopathy was first described in the late 1960s

These individuals show blunted systolic and diastolic contractile responses , ventricular hypertrophy or chamber dilatation, and electrophysiological abnormalities including prolonged QT intervals.

The pathogenesis of ths includes diminished β-adrenergic receptor signal transduction,cardiomyocyte cellular plasma membrane dysfunction, increased activity or levels of cardio- depressant substances such as cytokines, endogenous cannabinoids, and nitric oxide.

cirrhotic cardiomyopathy may contribute to the pathogenesis of hepatorenal syndrome precipitated by spontaneous bacterial peritonitis, acute heart failure after insertion of transjugular intrahepatic portosystemic shunts, and increased cardiovascular associated morbidity and mortality after liver transplantation.

Kim MY, Baik SK. Cirrhotic cardiomyopathy. Korean J Hepatol 2007; 13:20-26.

Kidney

Renal vasoconstriction is characteristic in kidney with splanchnic vasodilation and hyperdynamic circulation, and may be responsible for the development of hepatorenal syndrome.Renal vasoconstriction develops as a consequence of effective hypovolemia and ensuing neurohumoral activation.This provides the rationale for treating hepatorenal syndrome with albumin infusion and vasoconstrictors (terlipressin, norepinephrine, or midodrine)

Arroyo V et al. Ascites and hepatorenal syndrome in cirrhosis: J Hepatol 2003;38(Suppl 1):S69-S89.

Lung

Vasodilatation in the lung leads to ventilation perfusion mismatch and even arterio-venous shunts in the pulmonary circulation; these result in hepatopulmonary syndrome, characterized by marked hypoxemia. In some cases, this may evolve into the opposite situation with markedly increased pulmonary vascular resistance seen in portopulmonary hypertension.This is thought to develop through endothelial dysfunction and vascular remodeling of the pulmonary circulation

Rodriguez-Roisin R, Pulmonary-Hepatic vascular Disorders (PHD). Eur Respir J 2004;24:861-880.

Brain

cerebral blood flow and vascular reactivity associated with portal hypertension are considered to contribute and facilitate some of the brain abnormalities of hepatic encephalopathy.

Classification of portal htn

Prehepatic resistancePrehepatic causes of increased resistance to flow include the following:•Portal vein thrombosis•Splenic vein thrombosis•Congenital atresia or stenosis of portal vein•Extrinsic compression (tumors)•Splanchnic arteriovenous fistula

Intrahepatic resistance•A reduction of sinusoidal caliber due to hepatocyte enlargement•An alteration in the elastic properties of the sinusoidal wall due to collagen deposition in the space of Disse•Compression of hepatic venules by regeneration nodules• Central vein lesions caused by perivenous fibrosis• Veno-occlusive changes ,Perisinusoidal block by portal inflammation, portal fibrosis, and piecemeal necrosis

More specifically, intrahepatic, predominantly presinusoidal causes of resistance to flow include the following:

Schistosomiasis (early stage) Primary biliary cirrhosis (early stage) Idiopathic portal hypertension (early stage) Nodular regenerative hyperplasiaMyeloproliferative diseases Polycystic disease Hepatic metastasis Granulomatous diseases (sarcoidosis, tuberculosis)

Intrahepatic, predominantly sinusoidal causes of resistance include the following:• Hepatic cirrhosis• Acute alcoholic hepatitis• Schistosomiasis (advanced stage)• Primary biliary cirrhosis (advanced stage)• Idiopathic portal hypertension (advanced stage)• Acute and fulminant hepatitis• Congenital hepatic fibrosis• Peliosis hepatitis

• Vitamin A toxicity• Sclerosing cholangitis• Hepatitis B virus–related and hepatitis C virus–related cirrhosis• Wilson disease• Hemochromatosis• Alpha-1 antitrypsin deficiency• Chronic active hepatitis

Postsinusoidal obstruction syndrome veno-occlusive disease of the liver

Postsinusoidal causes of resistance

Posthepatic resistanceThrombosis of the inferior vena cava (IVC) Right-sided heart failure Constrictive pericarditis Severe tricuspid regurgitation Budd-Chiari syndrome Arterial-portal venous fistula Increased portal blood flow Increased splenic flow

Extra Hepatic Portal Vein Obsrtuction

• Portal hypertension caused by EHPVO occurs when the site of block is in the portal vein before the blood reaches the liver.

• EHPVO is a vascular disorder of the liver.

• It is defined by obstruction of the extra-hepatic portal vein with or without involvement of the intra-hepatic portal veins or splenic or superior mesenteric veins.

• Isolated occlusion of the splenic vein or superior mesenteric vein does not constitute EHPVO.

• Portal vein obstruction associated with chronic liver disease or neoplasia is a separate entity and does not constitute EHPVO.

Sarin et al , Liver International 2006: 26: 512–519

PrevalenceEHPVO is a common cause of portal hypertension in the developing countries (up to 30% of all variceal bleeders) and is second to cirrhosis in the West (up to 5–10%) . EHPVO is also the most common cause of upper gastrointestinal bleeding in children. It accounts for almost 70% of pediatric patients with portal hypertension

Khandur A et al , Gastrointestinal bleeding in children. J Gastroenterol Hepatol 1996; 11: 903–7.

• EHPVO is a heterogenous disease with regard to etiology and pathogenesis,especially with respect to age and geographical location.

Children• Evidence of umbilical sepsis, umbilical

catheterization and intra-abdominal sepsis • Congenital anomalies • hypercoagulable disorder in children

Adults Underlying hypercoagulable and prothrombotic states are common Intra-abdominal inflammatory pathology and trauma.

EHPVO could also be secondary to liver cirrhosis and neoplasia, but it is considered with respect to the primary disease itself

Childhood EHPVO

The typical presenting symptoms are repeated episodes of variceal bleeding and a feeling of a lump in the abdomen. Variceal bleeding: The usual presentation for children with EHPVO is sudden, unexpected and, often, massive hemetemesis, recurrent, well-tolerated bleeds without significant hepatocellular failure are common.Growth retardation: EHPVO occurring in the pre-pubertal period could result in growth retardation in around 50% of the children.Ascitis

Sherlock S. The etiology, presentation and natural history of extra-hepatic portal venous obstruction. Q J Med 1979; 192: 627–39.

Adult EHPVOThe presentation could be either acute (recent) or chronic EHPVO.Acute or recent EHPVO: These patients often present with acute abdominal pain. pain could sometimes accompanied by fever and, rarely, ascites. Chronic: Variceal bleeding and hypersplenism are the common manifestations. Ectopic varices in EHPVO: These are reported in 27–40% of patients with EHPVO, and are commonly seen in the duodenum, anorectal region and gallbladder bed Hepatic encephalopathyIntestinal ischemiaJaundice

Sarin et al , Liver International 2006: 26: 512–519

EHPVO and pregnancy• This is a peculiar situation where there is an apparent

threat to the mother and baby. • The risk of variceal bleeding in pregnant EHPVO patients

is higher than in pregnant cirrhotic women. While the maternal outcome following a variceal bleed in pregnant EHPVO patients is good, the fetal outcome is poor.

• The incidences of abortion, pre-maturity, small for gestational age babies and perinatal death are high in pregnant patients with EHPVO

Hemodynamics in EHPVO• Hepatic vein pressure gradient is normal in

EHPVO .• Intravariceal and intrasplenic pressures closely

reflect portal pressure. These are elevated in EHPVO patients and suggest portal hypertension

• Currently, portal pressure measurement has a limited role in the clinical management of patients with EHPVO

Sarin et al , Liver International 2006: 26: 512–519

NCPF - definition

• Disease of uncertain etiology • Portal fibrosis & invlv. small and

med.portal veins• Portal hypertension,splenomegaly,variceal

bleed.• Liver functions & stucture- normal

terminology

• Non –cirrhotic portal fibrosis by ICMR in 1969

• Idiopathic portal hypertension in Japan

• Hepato portal sclerosis in West

• In India, NCPF constituted 7.9 to 46.7% of patients with portal hypertension, with a peak age of third and fourth decades of life.

• A majority of patients belongs to lower socioeconomic strata.• no sex predilection • although the study from Chandigarh shows a female

predominance.

• Dhiman RK, et al. Noncirrhotic portal fibrosis experience with 151 patients and a review of the literature. J Gastroenterol Hepatol 2002;17:6–16

• IPH in Japan, in contrast has been reported to have a female preponderance, with a peak age one to two decades older than patients with NCPF.

etiology• Infections – bacterial inf. From gut. - umblical sepsis,diarrhoea in infancy & early childhood.• TOXINS AND DRUGS :chronic exposure to copper sulfate :

chronic arsenicosis , vinyl chloride nmonomers • Auto- immune disorders.• Pro-thrombotic state (west). • protracted treatment with methotrexate, 6-mercaptopurine,

azathioprine, prednisolone irradiation and chemotherapy• hypervitaminosis A• Exact etiology is still unknown

Clinical Features

• Three-fourths of NCPF patients in India present with well-tolerated upper gastrointestinal bleeding. Awareness of a mass in the left hypochondrium (hypersplenism) The spleen is massively enlarged, almost reaching the umbilicus.

• Ascites is uncommon, and may occur after an episode of gastrointestinal bleeding (9.9%).

Sarin SK. Noncirrhotic portal fibrosis a clinical profile of 366 patients. Am J Gasteroenterol 2006; 101:S19

• IPH patients mainly present with splenomegaly in 88% of patients,

• Gastrointestinal bleeding in 35%. • Ascites in 12%.• Thrombosis of portal vein may be seen in several

cases. Okuda K, et al. Idiopathic Portal Hypertension: a natural study. In:Hepatology a festschrift

for Hans Popper. NewYork: Raven Press;1985:95–108

NCPF vs IPHNCPF IPH

Age (years) 25-35 43-56

M: F 1:1 1:3

Hemetemesis/ malena 94 % 40%

Spenomegaly Dispropationate & massive

moderate

Autoimmune features rare common

Wedge hepatic venous pressure

normal Mildly raised

Geography Indian subcontinent Japan

parameter EHPVO NCPF Cirrhosis

Median age 10 yr 28 yr 40 yr

Ascites Absent/transientafter bleed

Absent/transient after bleed

+ to +++

Encephalopathy nil nil ++

Jaundice/signs of liver failure

nil nil ++

Liver function test normal normal deranged

Liver –Gross normal normal Shrunken,nodular

microscopic normal Normal/portal fibrosis

Necrosis,regeneration

Usg Portal/splenic vein block & cavernoma

dilated & patent&thickenedSpleno-portal axis

Dilated & patentSpleno-portal axis

Budd-Chiari Syndrome

• Caused by hepatic venous obstruction• At the level of the inferior vena cava, the

hepatic veins, or the central veins within the liver itself

• result of congenital webs (in Africa and Asia), acute or chronic thrombosis (in the West), and malignancy

Budd-Chiari Syndrome

• Acute symptoms include hepatomegaly, RUQ abdominal pain, nausea, vomiting, ascites

• Chronic form present with the sequelae of cirrhosis and portal hypertension, including variceal bleeding, ascites, spontaneous bacterial peritonitis, fatigue, and encephalopathy

epidemology• m:f 1:2• 3rd and 4th decade• Median age – 35

• Location Hepatic vein 62%IVC 7%Both IVC & hepatic veins 31%Associated portal vein thrombus 14%

Pathogenesis HEPATIC VEIN THROMBOSIS

Sinusoidal pressure

Sinusoidal flow

Sinusoidal dilatation+Interstitial fluid filtration

Fluid passes through hepatic capsule(Ascitis)

portal vein pressure & perfusion of liver via portal vein

Hypoxia of hepatocyte

inflammatory centrilobular cell necrosis

Release of free oxygen radicals

Atrophy

chronic weeks of obstruction

fibrosis of centrilobar area

nodular regeneration in periportal area

cirrhosis portovenous . collateral

cirrhosis

Etiology:•  majority of patients have an underlying

hematologic abnormality. • Tumor

– Hepatocellular carcinoma– Carcinoma of pancreas– Carcinoma of kidneys– Metastatic disease