Pathophysiology of Portal Hypertension

1
Pathophysiology of Portal Hypertension

• By
• Mohammad S Abdel Bary, MD
• Lecturer of Tropical Medicine
• Cairo University

2

• PH is defined as an increase in pressure gradient
  between the portal vein and the hepatic veins or
  IVC (Bosch, 1992).
• A pressure gradient of 12 mm Hg is regarded as
  clinically significant for PH.

3

• According to Ohms law (P Q x R), portal venous
  pressure is proportional to blood flow and
  resistance P is the change in portal pressure
  along the vessel, Q is portal blood flow, and R
  is the resistance to flow.
• In the normal liver, intrahepatic resistance
  changes with variations in portal blood flow,
  thereby keeping portal pressure within normal
  limits.

4

• The causes of PH can be divided into (1)
  post-hepatic, (2) pre-hepatic, and (3)
  intra-hepatic causes.
• The major causes of posthepatic causes of PH are
  right-sided heart failure, constrictive
  pericarditis, and Budd-Chiari syndrome (BCS).
• The prehepatic causes of PH include portal vein
  thrombosis (PVT) and portal compression or
  occlusion by biliary and pancreatic neoplasms and
  metastases. PH may be caused by increased flow
  secondary to arterioportal fistula, pancreatic
  arteriovenous malformations, and massive
  splenomegaly.
• The most common intrahepatic cause is cirrhosis.

5

• The sinusoids lack a basement membrane and are
  loosely surrounded by specialist fenestrated
  endothelial cells and kupffers cells (phagocytic
  cells).
• Sinusoids are separated by plates of liver cells
  (hepatocytes).
• The subendothelial space that lies between the
  sinusoids and hepatocytes is the space of Disse
  which contains a matrix of basement membrane
  constituents and stellate cells.

6

• Stellate cells (previously called fat storage
  cells or Ito cells store retinoids (vitamin A)
  and contain the intermediate filament, desmin.
  They are contractile and probably regulate
  sinusoidal blood flow.
• Endothelin and nitric oxide play an important
  role in modulating stellate cell contractility.

7
Increased Resistance To Portal Flow
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• Chronic injury to the liver results in
  inflammation, necrosis and, eventually, fibrosis.
  
• Fibrosis is intiated by activation of the
  stellate cells.
• In the early stage of activation the stellate
  cells become swollen and lose retinoids with
  up-regulation of receptors for proliferative and
  fibrogenic cytokines, such as platelet-derived
  growth factor (PDGF), and transforming growth
  factor ?1 (TGF?1) which is the most potent
  fibrinogenic mediator identified so far.

9

• During liver injury, stellate cells are activated
  and transform into myofibroblasts.
• In these cells there is de novo expression of the
  specific smooth muscle protein ?-actin.
• Under the influence of mediators, such as
  endothelin, nitric oxide or prostaglandins, the
  contraction of these activated cells contributes
  to abnormal blood flow patterns and increased
  resistance to blood flow.

10

• Fibrogenesis is characterized by an upregulation
  of collagen synthesis, a downregulation of
  ECM-degrading enzymes (The matrix
  metalloproteinases, MMPs) and by an increase of
  the physiological inhibitors of the MMPs, the
  tissue inhibitors of MMPs (TIMPs).
• Among the four known TIMPs, the universal
  MMP-inhibitor TIMP-1 is the most important.
  Importantly, collagens as well as MMPs and TIMPs
  are mainly produced by the fibrogenic cells
  themselves, i.e. activated hepatic stellate cells
  (HSC) and (portal, perivenular) myofibroblasts
  (MF).

11

• In the space of Disse, the normal matrix is
  replaced by collagens, predominantly types 1 and
  3, and fibronectin. Subendothelial fibrosis leads
  to loss of the endothelial fenestrations (ports),
  and this impairs liver function.

12
Increased Portal Blood Flow
13

• This increased resistance leads to portal
  hypertension and opening of portosystemic
  anastomoses in both pre-cirrhotic and cirrhotic
  livers. Patients with cirrhosis have a
  hyperdynamic circulation.
• This is thought to be due to the release of
  mediators, such as nitric oxide and glucagon,
  which leads to peripheral and splanchnic
  vasodilatation.
• This effect is followed by plasma volume
  expansion due to sodium retention , and this has
  a significant effect in maintaining portal
  hypertension.