Fibrosis hepatis

The development of hepatic fibrosis reflects an alteration in the normally balanced processes of
extracellular matrix production and degradation.[4] The extracellular matrix, the normal
scaffolding for hepatocytes, is composed of collagens (especially types I, III, and V),
glycoproteins, and proteoglycans.
Stellate cells, located in the perisinusoidal space, are essential for the production of extracellular
matrix. Stellate cells, which were once known as Ito cells, lipocytes, or perisinusoidal cells, may
become activated into collagen-forming cells by a variety of paracrine factors. Such factors may
be released by hepatocytes, Kupffer cells, and sinusoidal endothelium following liver injury. As
an example, increased levels of the cytokine transforming growth factor beta1 (TGF-beta1) are
observed in patients with chronic hepatitis C and those with cirrhosis. TGF-beta1, in turn,
stimulates activated stellate cells to produce type I collagen.
In a study that evaluated serum cytokine levels between healthy patients, those with
stable cirrhosis, and patients with decompensated cirrhosis with and without development of
acute-on-chronic liver failure (ACLF), Dirchwolf et al found the presence of distinct cytokine
phenotypes was associated with cirrhosis severity.[5] Relative to the healthy patients, those with
cirrhosis had elevated levels of proinflammatory cytokines (interleukin [IL]-6, -7, -8, -10, and
-12, and tumor necrosis factor-alpha [TNF-]) and chemoattractant elements. Leukocyte count
was positively correlated with disease severity across the scoring systems used, levels of IL-6
and IL-8 had positive correlation with Model for End-Stage Liver Disease (MELD) score, and
IL-6 alone had a positive correlation with chronic liver failure-sequential organ failure
assessment (Clif-SOFA) score at day 7 (but a negative correlation with IL-2 at admission).[5]
Increased collagen deposition in the space of Disse (the space between hepatocytes and
sinusoids) and the diminution of the size of endothelial fenestrae lead to the capillarization of
sinusoids. Activated stellate cells also have contractile properties. Capillarization and
constriction of sinusoids by stellate cells contribute to the development of portal hypertension.
Future drug strategies to prevent fibrosis may focus on reducing hepatic inflammation, inhibiting
stellate cell activation, inhibiting the fibrogenic activities of stellate cells, and stimulating matrix
degradation.

Portal Hypertension
The normal liver has the ability to accommodate large changes in portal blood flow without
appreciable alterations in portal pressure. Portal hypertension results from a combination of
increased portal venous inflow and increased resistance to portal blood flow.
Patients with cirrhosis demonstrate increased splanchnic arterial flow and, accordingly, increased
splanchnic venous inflow into the liver. Increased splanchnic arterial flow is explained partly by
decreased peripheral vascular resistance and increased cardiac output in the patient with
cirrhosis. Nitric oxide appears to be the major driving force for this phenomenon.[6]
Furthermore, evidence for splanchnic vasodilation exists. Putative splanchnic vasodilators
include glucagon, vasoactive intestinal peptide, substance P, prostacyclin, bile acids, tumor
necrosis factor-alpha (TNF-alpha), and nitric oxide.
Increased resistance across the sinusoidal vascular bed of the liver is caused by fixed factors and
dynamic factors. Two thirds of intrahepatic vascular resistance can be explained by fixed
changes in the hepatic architecture. Such changes include the formation of regenerating nodules
and, after the production of collagen by activated stellate cells, deposition of the collagen within
the space of Disse.
Dynamic factors account for one third of intrahepatic vascular resistance. Stellate cells serve as
contractile cells for adjacent hepatic endothelial cells. The nitric oxide produced by the
endothelial cells, in turn, controls the relative degree of vasodilation or vasoconstriction
produced by the stellate cells. In cirrhosis, decreased local production of nitric oxide by
endothelial cells permits stellate cell contraction, with resulting vasoconstriction of the hepatic
sinusoid. (This contrasts with the peripheral circulation, where there are high circulating levels of
nitric oxide in cirrhosis.) Increased local levels of vasoconstricting chemicals, such as
endothelin, may also contribute to sinusoidal vasoconstriction.
The portal hypertension of cirrhosis is caused by the disruption of hepatic sinusoids. However,
portal hypertension may be observed in a variety of noncirrhotic conditions.
Prehepatic causes
Prehepatic causes include splenic vein thrombosis and portal vein thrombosis. These conditions
commonly are associated with hypercoagulable states and with malignancy (eg, pancreatic
cancer). In a retrospective study (2002-2014) of 66 patients with cirrhosis and portal vein
thrombosis, Chen et al reported that warfarin anticoagulation may potentially safely and
effectively resolve cases of more advanced portal vein thrombosis.[7] However, they did not
observe any benefit of anticoagulation on decompensation or mortality. Levels of albumin were
significant predictors of decompensated disease at 1 year.[7]
Intrahepatic causes

Intrahepatic causes of portal hypertension are divided into presinusoidal, sinusoidal, and
postsinusoidal conditions. The classic sinusoidal cause of portal hypertension is cirrhosis.
The classic form of presinusoidal portal hypertension is caused by the deposition of Schistosoma
oocytes in presinusoidal portal venules, with the subsequent development of granulomata and
portal fibrosis. Schistosomiasis is the most common noncirrhotic cause of variceal bleeding
worldwide. Schistosomamansoni infection is described in Puerto Rico, Central and South
America, the Middle East, and Africa. S japonicum is described in the Far East. S hematobium,
observed in the Middle East and Africa, can produce portal fibrosis but more commonly is
associated with urinary tract deposition of eggs.
The classic postsinusoidal condition is an entity known as veno-occlusive disease. Obliteration
of the terminal hepatic venules may result from ingestion of pyrrolizidine alkaloids in Comfrey
tea or Jamaican bush tea or following the high-dose chemotherapy that precedes bone marrow
transplantation.
Posthepatic causes
Posthepatic causes of portal hypertension may include chronic right-sided heart failure and
tricuspid regurgitation and obstructing lesions of the hepatic veins and inferior vena cava. The
latter conditions, and the symptoms they produce, are termed Budd-Chiari syndrome.
Predisposing conditions include hypercoagulable states, tumor invasion into the hepatic vein or
inferior vena cava, and membranous obstruction of the inferior vena cava. Inferior vena cava
webs are observed most commonly in South and East Asia and are postulated to be due to
nutritional factors.
Symptoms of Budd-Chiari syndrome are attributed to decreased outflow of blood from the liver,
with resulting hepatic congestion and portal hypertension. These symptoms include
hepatomegaly, abdominal pain, and ascites. Cirrhosis ensues only later in the course of disease.
Differentiating Budd-Chiari syndrome from cirrhosis by history or physical examination may be
difficult. Thus, Budd-Chiari syndrome must be included in the differential diagnosis of
conditions that produce ascites and varices.
Hepatic vein patency is checked most readily by performing abdominal ultrasonography, with
Doppler examination of the hepatic vessels. Abdominal computed tomography (CT) scanning
with intravenous (IV) contrast, abdominal magnetic resonance imaging (MRI), and visceral
angiography also may provide information regarding the patency of hepatic vessels.
Kondo et al have reported that portal hemodynamics on Doppler ultrasonography may provide
noninvasive prognostic implications for decompensation and long-term outcomes in patients
with cirrhosis.[8] In their retrospective study of 236 cirrhotic patients (compensated, n = 110;
decompensated, n = 126) (mean followup, 33.2 mo), a significant predictor for the presence of
decompensation was baseline higher model for end-stage liver disease (MELD) score; moreover,
signficant prognostic factors for developing cirrhosis included higher alanine transaminase
levels, lower albumin levels, and lower mean velocity in the portal trunk.[8] For compensated

patients, significant predictors were hepatocellular carcinoma and lower albumin levels, whereas
in decompensated patients, they were elevated bilirubin levels and overt ascites.[8]

Measurement
Widespread use of the transjugular intrahepatic portosystemic shunt (TIPS) procedure in the
1990s for the management of variceal bleeding led to a resurgence of clinicians' interest in
measuring portal pressure. During angiography, a catheter may be placed selectively via either
the transjugular or transfemoral route into the hepatic vein. In the healthy patient, free hepatic
vein pressure (FHVP) is equal to inferior vena cava pressure. FHVP is used as an internal zero
reference point.
Wedged hepatic venous pressure (WHVP) is measured by inflating a balloon at the catheter tip,
thus occluding a hepatic vein branch. Measurement of the WHVP provides a close
approximation of portal pressure. The WHVP actually is slightly lower than the portal pressure
because of some dissipation of pressure in the sinusoidal bed. The WHVP and portal pressure are
elevated in patients with sinusoidal portal hypertension, as is observed in cirrhosis.

Complications
The hepatic venous pressure gradient (HVPG) is defined as the difference in pressure between
the portal vein and the inferior vena cava. Thus, the HVPG is equal to the WHVP value minus
the FHVP value (ie, HVPG = WHVP - FHVP). The normal HVPG is 3-6 mm Hg.
Portal hypertension is defined as a sustained elevation of portal pressure above normal. An
HVPG of 8 mm Hg is believed to be the threshold above which ascites potentially can develop.
An HVPG of 12 mm Hg is the threshold for the potential formation of varices. High portal
pressures may predispose patients to an increased risk of variceal hemorrhage.[9]