Book on hepatitis from page 508 to 521

Book on hepatitis from page 508 to 521

508  Hepatology 2012
Vento S, Guella L, Mirandola F, et al. Epstein-Barr virus as a trigger for autoimmune hepatitis in
susceptible individuals. Lancet 1995;346:608-9. (Abstract)
Vogel A, Heinrich E, Bahr MJ, et al. Long-term outcome of liver transplantation for autoimmune
hepatitis. Clin Transplant 2004;18:62-69. (Abstract)
Vogel A, Liermann H, Harms A, et al. Autoimmune regulator AIRE: Evidence for genetic
differences between autoimmune hepatitis and hepatitis as part of the autoimmune
polyglandular syndrome type 1. Hepatology 2001;33:1047-52. (Abstract)
Vogel A, Manns MP, Strassburg CP. Autoimmunity and viruses. Clin Liver Dis 2002;6:451-5
(Abstract)
Vogel A, Strassburg CP, Manns MP. 77 C/G Mutation in the Tyrosine Phosphatase CD45 and
Autoimmune Hepatitis: Evidence for a Genetic Link. Genes and Immunity 2003;4:79-81. (Abstract)
Vogel A, Strassburg CP, Manns MP. Genetic association of vitamin D receptor polymorphisms
with primary biliary cirrhosis and autoimmune hepatitis. Hepatology 2002;35:126-31.
(Abstract)
Volkmann M, Martin L, Baurle A, et al. Soluble liver antigen: isolation of a 35-kd recombinant
protein (SLA-p35) specifically recognizing sera from patients with autoimmune
hepatitis. Hepatology 2001;33:591-6. (Abstract)
Waldenström J. Leber, Blutproteine und Nahrungseiweisse. Dtsch Gesellsch Verd Stoffw 1950;
15:113-9. (Abstract)
Warnes TW, Smith A, Lee FI, et al. A controlled trial of colchicine in primary biliary cirrhosis.
Trial design and preliminary report. J Hepatol 1987;5:1-7. (Abstract)
Weismüller TJ, Wedemeyer J, Kubicka S, et al. The challenges in primary sclerosing
cholangitis - Aetiopathogenesis, autoimmunity, management and malignancy. J
Hepatol 2008;48:S38-S57. (Abstract)
Wesierska-Gadek J, Hohenuer H, Hitchman E, et al. Autoantibodies against nucleoporin p62
constitute a novel marker of primary biliary cirrhosis. Gastroenterology 1996;110:840-7. (Abstract)
Wies I, Brunner S, Henninger J, et al. Identification of target antigen for SLA/LP autoantibodies
in autoimmune hepatitis [see comments]. Lancet 2000;355:1510-5. (Abstract)
Wiesner RH, Grambsch PM, Dickson ER, et al. Primary sclerosing cholangitis: natural history,
prognostic factors and survival analysis. Hepatology 1989;10:430-6. (Abstract)
Wiesner RH, Ludwig J, Lindor KD, et al. A controlled trial of cyclosporine in the treatment of
primary biliary cirrhosis. N Engl J Med 1990;322:1419-24. (Abstract)
Wiesner RH, Porayko MK, Dickson ER, et al. Selection and timing of liver transplantation in
primary biliary cirrhosis and primary sclerosing cholangitis. Hepatology
1992;16:1290-9. (Abstract)
Wolfhagen FHJ, Van Hoogstraaten HJF, Van Buuren HR. Triple therapy with ursodeoxycholic
acid, prednisone, and azathioprine in primary biliary cirrhosis: a 1 year randomized,
placebo controlled study. J Hepatol 1998;29:736-42. (Abstract)
Worman HJ. Primary biliary cirrhosis and the molecular cell biology of the nuclear envelope. Mt
Sinai J Med 1994;61:461-75. (Abstract)
Wright Hl, Bou-Abboud CF, Hassanenstein T, et al. Disease recurrence and rejection following
liver transplantation for autoimmune chronic active liver disease. Transplantation
1992;53:136-9. (Abstract)
Zanger UM, Hauri HP, Loeper J, et al. Antibodies against human cytochrome P-450db1 in
autoimmune hepatitis type 2. Proc. Natl. Acad. Sci. USA 1988;85:8256-60. (Abstract)
Zuchner D, Sternsdorf T, Szostecki C, et al. Prevalence, kinetics, and therapeutic modulation of
autoantibodies against Sp100 and promyelocytic leukemia protein in a large cohort of
patients with primary biliary cirrhosis. Hepatology 1997;26:1123-30. (Abstract)
Vascular Liver Disease  509
29. Vascular Liver Disease
Matthias J. Bahr
“It is impossible to explain or to understand the morbid appearances of the liver,
without referring to its intimate structure, and as some points relating to this have
been only lately made out, I shall commence with a short account of it.”
Georg Budd, Diseases of the Liver, 1853
Vascular liver diseases comprise a heterogeneous group of mostly rare hepatic
disorders – some of them exceedingly rare. This is why most of the evidence
regarding diagnosis and management results from retrospective and prospective
cohort studies rather than from randomized controlled trials.
Every single part of the hepatic vasculature may be affected, i.e., hepatic
sinusoids, portal vein, hepatic artery and liver veins. The clinical presentation varies
widely depending on the type of disease but also within the individual disease
entities. Vascular liver diseases may present as acute disorders or chronic liver
disease, as hepatocellular necrosis or cholestasis, as tumour-like lesions or portal
hypertension.
The spectrum of underlying causes is wide, and in many cases multiple risk
factors will result in the development of clinically significant disease (Table 1).
Disorders of the hepatic sinusoid
Hepatic sinusoidal disease may present as luminal obstruction (i.e., sinusoidal
obstruction syndrome), as luminal enlargement (i.e., peliosis hepatis) or as
perisinusoidal fibrosis. Whether the latter should be regarded as a separate disease
entity is debatable, as perisinusoidal fibrosis may also be observed as a histological
feature of common diseases such as steatohepatitis. Both sinusoidal obstruction
syndrome as well as peliosis hepatis are not strictly confined to the hepatic sinusoids
but may extend to the hepatic venous system.
Sinusoidal obstruction syndrome
Sinusoidal obstruction syndrome (SOS), previously referred to as hepatic
venooclusive disease (VOD), is a circulatory disorder primarily affecting the hepatic
sinusoids. Involvement of the hepatic central veins may occur, but studies after
conditioning for hematopoietic cell transplantation have demonstrated that in more
510  Hepatology 2012
than 40% of patients with SOS the hepatic venous system is not involved. The
proportion of sole sinusoidal affection falls to 25% in patients with severe SOS
(DeLeve 2009).
Table 1. Classification of predisposing factors for vascular liver disease.
Hereditary disorders    •  Inherited thrombophilia, e.g., factor V Leiden mutation, mutations
of prothrombin, protein C, protein S, antithrombin III
•  Hereditary hemorrhagic teleangiectasia
Congenital
malformations
•  Webs, shunts, aneurysms
Acquired cellular
defects
•  Myeloproliferative disease
•  Paroxysmal nocturnal hemoglobinuria
•  Malignancy
Inflammatory disease
& immune mediated
disorders
•  Focal inflammatory lesions causing thrombosis, e.g., pancreatitis,
diverticulitis, appendicitis, cholecystitis, abscesses, inflammatory
bowel disease
•  Vasculitis, e.g., polyarteritis nodosa, Behçet syndrome
•  Rheumatic disease
Infectious diseases    •  Schistosomiasis
•  Bacillary angiomatosis (Bartonella h.)
Miscellaneous    •  Drugs, e.g., oral contraceptives, azathioprine, chemotherapy
•  Pregnancy
•  Cirrhosis
•  Radiation
Pathophysiology
Although many risk factors may be complicated by sinusoidal obstruction
syndrome, the by far most common cause in the Western world are myeloablative
regimens in the preparation for hematopoietic stem cell transplantation (HSCTx),
particularly when the transplant is for a malignancy. The proportion of patients with
SOS after HSCTx varies from the single-digit percentage range up to 50% if highly
toxic regimens are chosen. Apart from conditioning regimens for HSCTx (high-dose
chemotherapy plus total body irradiation), other drugs have been implicated in the
development of SOS (Table 2). Originally, the syndrome was described in
conjunction with the ingestion of herbal teas or foods containing pyrrolizidine
alkaloids.
Both the histopathological changes and the clinical picture of SOS were
experimentally studied in a rat model using monocrotaline, a pyrrolizidine alkaloid
that is directly toxic to sinusoidal endothelial cells. These experiments have
confirmed the primary sinusoidal damage infrequently followed by central venous
involvement (DeLeeve 1996).
Clinical presentation and diagnosis
The characteristic clinical presentation of patients with SOS is weight gain-associated or not with ascites, hepatomegaly with right upper quadrant pain, and
jaundice. The onset of symptoms usually occurs between day 10 and day 20 after
cyclophosphamide-containing regimens but can be delayed up to 1 month after
conditioning therapy if other therapies are used.
Severity of SOS varies from mild forms that just meet the diagnostic criteria to
rapidly progressing and eventually life-threatening disease (McDonald 1993). In
Vascular Liver Disease  511
patients not requiring treatment of fluid excess or hepatic pain, SOS is considered
mild and is associated with a self-limiting course. Treatment associated with a
complete remission within 100 days is considered moderate disease. If SOS does
not resolve by day 100, it is categorized as severe. This classification, however, is
retrospective and does not support clinical decision-making.
Table 2. Drugs associated with sinusoidal obstruction syndrome
•  6-mercaptopurine
•  6-thioguanine
•  Actinomycin D
•  Azathioprine
•  Busulfan*
•  Cytosine arabinoside
•  Cyclophosphamide*
•  Dacarbazine
•  Gemtuzumab-ozogamicin
•  Melphalan*
•  Oxaliplatin
•  Urethane
* Exclusively reported with conditioning regimens for HSCTx (modified
according to DeLeve 2009)
Primarily, SOS is a clinical diagnosis with the following characteristics: (1)
hepatotoxic conditioning regimen for HSCTx with an appropriate temporal relation
to the development of clinical signs and symptoms, (2) weight gain & hepatic pain
& jaundice and, (3) negative work-up for other causes. In patients meeting these
criteria, diagnosis can be made with reasonable certainty and solely  based on
clinical judgement. Differential diagnoses comprise cholestatic jaundice due to
sepsis, drug-induced cholestasis, fluid overload due to renal failure or congestive
heart failure, liver involvement by viral or fungal infections, and acute graft-versus-host disease. However, in up to 20% of patients the diagnosis of SOS cannot be
reliably made on clinical grounds (McDonald 1993 & 2004). This has promoted the
development of scoring systems such as the Seattle or the Baltimore Criteria (Jones
1987; McDonald 1993) (Table 3). However, up to 50% of patients not meeting the
Baltimore criteria may exhibit histological features of SOS (Shulman 1994).
Table 3. Clinical diagnosis of sinusoidal obstruction syndrome after HSCTx.
Seattle criteria (McDonald 1993)  Baltimore criteria (Jones 1987)
At least two of the following findings within 20
days of transplantation:*
● Bilirubin >34.2 µmol/L (2 mg/dL)
● Hepatomegaly or right upper quadrant pain of
liver origin
● ≥2% weight gain due to fluid accumulation
Hyperbilirubinemia >34.2 µmol/L (2 mg/dL)
plus ≥2 additional criteria
● Usually painful hepatomegaly
● ≥5% weight gain
● Ascites
* The 20-days rule applies to cyclophosphamide containing regimens, should be adjusted
according to the regimen actually used.
The gold standard to confirm SOS is based on the combination of hepatic
histology plus measurement of the wedged hepatic venous pressure gradient (HVPG
512  Hepatology 2012
>10 mmHg, specificity >90%, PPV >85%). Both can be achieved during a single
procedure via the transvenous route, especially as increased bleeding risk often
precludes percutaneous liver biopsy. However, histology may be negative due to the
sometimes patchy character of the disease. Imaging techniques are used to confirm
hepatomegaly or ascites and will help to rule out differential diagnoses such as
biliary obstruction. A more specific sign is the finding of hepatic inflow blockage
with reduced or reversed portal flow in colour Doppler ultrasound (Figure 1). In
addition, attenuation of hepatic venous flow or gallbladder wall edema may be
detected. Some authors suggest the use of composite imaging scores (Lassau 2002).
Figure 1. Doppler ultrasound in sinusoidal obstruction syndrome. Exemplary case
showing undulating portal venous flow in a jaundiced patient after HSCTx.
Management and prognosis
Taking into account that SOS is probably underdiagnosed solely employing clinical
criteria, case fatality rates of detected SOS vary between 15 and 20% (DeLeve
2009). Apart from deep jaundice additional signs of liver failure such as
coagulopathy or hepatic encephalopathy may be missing. In contrast, systemic
Vascular Liver Disease  513
complications leading to multiple organ failure (renal, pulmonary) are the main
reasons for death in these patients. This points to the necessity of a closely
supervised management concept. Highly toxic conditioning regimens should
possibly be avoided. Though commonly used, currently published data are too
scarce to endorse prophylactic therapy (e.g., ursodeoxycholic acid, heparin,
liposomal PGE2).
Several treatments have been suggested for established SOS, e.g., thrombolysis
using tPA or defibrotide. In addition, invasive strategies such as TIPS or liver
transplantation were evaluated. However, current knowledge is mainly based on
case reports or cohorts. Although current guidelines do not advise for or against
specific medical treatments, some recommendations can be made (DeLeve 2009).
First of all, fluid management should aim to control fluid overload (using diuretics,
paracentesis, hemofiltration/hemodialysis). Thrombolysis has not proved successful
and was associated with severe complications like bleeding. Several non-controlled
cohort studies suggested positive effects using defibrotide, a mixture of single-stranded oligodeoxyribonucleotides derived from porcine intestinal mucosa. Phase
II studies are completed (Richardson 2010) and Phase III studies are under way.
This compound can also be used in multiple organ failure without substantially
increasing the bleeding risk.
Unlike Budd-Chiari syndrome, decompression of portal hypertension using TIPS
does not improve SOS. For patients with favourable prognosis of the underlying
hematopoietic disorder after HSCTx, liver transplant might be considered.
Peliosis hepatis
Peliosis hepatis is a rare disorder characterized by single or multiple blood-filled
cystic cavities within the hepatic tissue. Prevalence may vary between 0.03% in
HIV infection, 0.2% in pulmonary tuberculosis and up to 20% after renal
transplantation. There is no favored localisation of the peliotic lesions and
appearance at all ages, including a fetal form, has been described. The size ranges
from submillimetres to centimetres but rarely exceeds 3 cm. The histopathological
appearance may show a missing endothelial cell lining with hepatocytes directly
serving as boundary (parenchymal type). In other cases the endothelium may be
preserved but the hepatic sinusoids appear dilated. The aneurysmal dilation may
extend to the central vein (phlebectatic type) (Yanoff 1964, Tsokos 2005).
Pathophysiology
Several risk factors have been accused to promote the development of peliosis
hepatis, e.g., infections, drugs or malignant disorders (Table 4). However, the exact
pathogenesis of peliosis hepatis is largely speculative. The histological appearance
suggests that endothelial damage leads to the destruction of the endothelial lining.
Other hypotheses favour an increased sinusoidal pressure resulting in the widening
of the sinusoidal lumen with consecutive destruction of the sinusoidal endothelium
or primary hepatocellular necrosis replaced by blood-filled cystic lesions. Fibrotic
changes and even liver cirrhosis as well as regenerative nodules may be found, but it
is unclear whether these features are directly linked to peliosis hepatis or whether
they are just coincidental.
Clinical presentation and diagnosis
In the majority of cases, peliosis hepatis is asymptomatic and incidentally detected
during hepatic imaging. On rare occasions, the peliotic cysts may rupture leading to
514  Hepatology 2012
intrahepatic or intraabdominal hemorrhage. Individual cases with overt liver disease
were reported, characterised by hepatomegaly, jaundice, ascites, portal hypertension
and liver failure. Extrahepatic manifestations may be found in organs of the
mononuclear phagocytic system (e.g., spleen, lymph nodes, bone marrow) but also
in lungs, kidneys, parathyroid or adrenal glands, or other parts of the gastrointestinal
tract.
Usually, peliosis hepatis is easily detected by imaging techniques. However,
discrimination between peliosis and other benign or malignant lesions may turn
difficult. Peliotic lesions miss a mass effect on the adjacent hepatic vasculature.
Blood flow within the lesion is slow, resulting in a hypodense appearance after
contrast application in CT. However, in some patients a ring-like accumulation of
contrast media may be present. Using MRI, low intensity is seen in T1-weighted
images while T2-weighted images show a high signal. Though imaging techniques
may assist the diagnosis of peliosis hepatis, a liver biopsy is often needed for final
confirmation. Wedged hepatic venography may also be diagnostic, but its use needs
a strong suspicion.
Table 4. Risk factors reported with peliosis hepatis.
Infections    •  Human immunodeficiency virus
•  Bartonella spp. (bacillary angiomatosis)
•  Tuberculosis
Drugs, toxins    •  Azathioprine, cyclosporine
•  Anabolic steroids, glucocorticoids, oral contraceptives,
tamoxifen
•  Vinyl chloride, arsenic, thorium oxide
Malignant and
benign tumours
•  Multiple myeloma, Waldenström disease
•  Hodgkin disease
•  Hepatocellular adenoma
Miscellaneous    •  Renal transplantation
•  Celiac disease, diabetes mellitus
•  No underlying disorder in up to 50%
Management and prognosis
In most cases, peliosis hepatis will not progress to symptomatic disease. Thus, in
these patients management has to concentrate on the identification and, if required,
treatment of the underlying disease. Causal treatment is the therapeutic mainstay
and leads to regression of the peliotic lesions in the majority of cases. However, in
individual cases surgery may be indicated if the risk of cyst rupture and consecutive
bleeding is estimated to be high. If liver failure and portal hypertension dominate
the clinical picture liver transplantation might be considered provided etiology does
not pose a contraindication.
Disorders of the hepatic artery
Pathologies involving the hepatic artery may lead to different clinical pictures
(Table 5, Figure 2).
Occlusion of the arterial lumen results in ischemia of the supplied tissue. Though
gross hepatocellular necrosis may follow, such as in ischemic hepatitis, preserved
portal venous oxygen supply often prevents the most devastating damage. In
Vascular Liver Disease  515
contrast to the hepatic parenchyma, the biliary system is exclusively supplied
arterially and, therefore, more susceptible to ischemic damage. Clinically, this may
present as an elevation of cholestasis-associated liver enzymes (e.g., gamma GT,
alkaline phosphatase). In more severe cases, structural damage to bile ducts may be
irreversible (i.e., ischemic cholangiopathy). Especially after orthotopic liver
transplantation ischemia type biliary lesions (ITBL) still pose a major challenge for
clinical management.
Table 5. Etiology of hepatic artery disease.
Obstruction or
destruction of the
hepatic artery
•  Hepatic artery embolism or thrombosis
•  Vasculitis
•  Sickle cell anemia
•  Hemolytic uremic syndrome
•  Chronic transplant rejection
Aneurysms    •  Congenital malformations
•  Polyarteritis nodosa (PAN)
•  Focal inflammation, trauma
Shunts    •  Congenital malformations
•  Hereditary hemorrhagic teleangiectasia
Figure 2. Spontaneous arterioportal shunt. Angiography in a patient with non-cirrhotic portal
hypertension. A small arterioportal shunt is detected by superselective catheterisation.
Apart from sequelae due to hepatic ischemia, hepatic artery disease may present
either as an aneurysm or as a shunt. Aneurysms of the hepatic artery are often
detected incidentally on imaging procedures. The majority are asymptomatic but
abdominal pain or – in rare cases – obstructive jaundice may develop. In a minority
of patients (about 20%) multiple aneurysms are present. Males are more often
516  Hepatology 2012
affected than women. The risk of rupture and subsequent hemorrhage is high and
may reach up to 80% – depending on the size of the aneurysm. Therefore, either
radiological intervention or surgery needs to be evaluated (Hulsberg 2011, Christie
2011).
In contrast to aneurysms, shunts involving the hepatic artery are predominantly
symptomatic. The spectrum of symptoms is wide including abdominal pain, portal
hypertension or signs of high-output heart failure. The therapeutic approach has to
be individualized including radiological interventions or surgical procedures.
Hereditary hemorrhagic teleangiectasia
(Osler-Weber-Rendu syndrome)
Hereditary hemorrhagic teleangiectasia (HHT) is a highly penetrant, autosomal
dominant disease showing a heterozygous prevalence between 1:5000 and 1:8000. It
is characterized by progressive and multivisceral development of arteriovenous
malformations (Govani 2009).
Mutations in several genes interacting with transforming growth factor (TGF)-β
receptor have been identified in HHT. According to the genes involved, different
subtypes can be discriminated:
•  HHT 1 (ENG coding for endoglin, chromosome 9q33-q34.1),
•  HHT 2 (ACVRL1 coding for activin A receptor type II-like kinase ALK-1,
chromosome 12q11-q14),
•  HHT 3 (gene not yet identified, chromosome 5q31.3-q32),
•  HHT 4 (gene not yet identified, chromosome 7p14),
•  Juvenile polyposis/HHT (SMAD4, chromosome 18q21.1).
Liver involvement may be found in all subtypes but appears to be more frequent
in HHT 2.  Though hereditary, HHT is characterized by marked intrafamilial
variation.
Clinical presentation and diagnosis
HHT is a multivisceral disease. Apart from the nasopharnyx and the gastrointestinal
tract, central nervous (~10%), pulmonary (~50%) and hepatic involvement occur at
high frequency. Accordingly, the spectrum of clinical disease is wide, e.g., anemia,
seizures, subarachnoid hemorrhage, paraplegia, transient ischemic attacks/stroke,
dyspnea, cyanosis, polycythemia, abdominal pain and hepatic abscesses. Symptoms
develop progressively throughout life. Telangiectasias appear before the age of 20
in half, before 40 in two-thirds of the patients. Thereafter it takes one or two
decades for the development of significant bleeding or symptomatic visceral
involvement (Plauchu 1989, Govani 2009).
The proportion of hepatic involvement in HHT is reported between 30 and 75%.
With the improvement of imaging technology over time, the reported incidence of
hepatic malformations increased. The clinical picture of liver involvement in HHT
depends on the predominant type of malformation (i.e., arterioportal vs.
arteriovenous shunts). Arteriovenous malformations increase cardiac output. In
individual cases up to 20 L/min may be reached. These patients suffer from high
output cardiac failure. In addition, symptoms of a mesenteric steal syndrome (e.g.,
postprandial abdominal pain) and signs of biliary ischemia (e.g., biliary abscesses)
may occur. As a consequence of ischemia, nodular regeneration of the liver
Vascular Liver Disease  517
develops (HHT-associated pseudocirrhosis). Arterioportal malformations will cause
portal hypertension with all its complications (Buscarini 2006, Garcia-Tsao 2000).
Diagnosis of HHT is made using the Curaçao criteria, 3 of 4 of which need to be
fulfilled (Shovlin 2000, Faughnan 2011):
−  recurrent spontaneous epistaxis,
−  telangiectasias, multiple and in typical localisation,
−  positive family history,
−  visceral arteriovenous malformations (lung, liver, brain, spine).
Every patient with HHT should be screened for hepatic vascular malformations.
Using Doppler ultrasound, screening is performed with high sensitivity and
specificity (Table 6) (Caselitz 2003). If hepatic involvement is confirmed, cardiac
output should be estimated (e.g., via echocardiography). Furthermore, patients must
be screened at regular intervals to detect complications such as development of
portal hypertension or biliary lesions.
Table 6. Ultrasound criteria for hepatic involvement in HHT*.
Major criteria    •  Dilated common hepatic artery >7 mm (inner diameter)
•  Intrahepatic arterial hypervascularization
Minor criteria    •  Vmax of the proper hepatic artery >110 cm/s
•  RI of the proper hepatic artery <0.60
•  Vmax of the portal vein >25 cm/s
•  Tortuous course of the extrahepatic hepatic artery
Facultative findings   •  Dilated portal vein >13 mm
•  Dilated liver veins >11 mm
•  Hepatomegaly >15 cm in midclavicular line
•  Nodular liver margin
* Two major criteria: definitive hepatic involvement in HHT, one major criterium
plus minor criteria: probable hepatic involvement (modified according to Caselitz
2003)
Management of hepatic involvement in HHT
Currently, no established medical therapy for HHT exists. In chronic GI bleeding
the use of hormonal therapy (estrogen-progesterone preparations, danacrine), anti-fibrinolytics (aminocaproic acid, tranexamic acid) and other experimental drugs
(tamoxifen, interferon, thalidomide, sirolimus) were suggested (Faughnan 2011).
However, no data supports the use of these drugs to treat hepatic vascular
malformations.
Limited data exist for the use of hepatic artery embolisation and liver
transplantation (Buscarini 2006, Chavan 2004). Due to the invasiveness and
complication rates of these approaches only patients with moderate to severe
symptoms should be regarded as candidates for therapeutic interventions. Hepatic
artery embolisation can be used to reduce shunt flow in patients with arteriovenous
hepatic shunts. Thus, a significant reduction of cardiac output with improvement of
associated symptoms can be achieved. However, complications such as hepatic and
biliary necrosis or acute cholecystitis have been described. Success of hepatic artery
embolisation very much depends on adequate patient selection. Current guidelines
do not endorse general use of embolisation outside of experienced centres but do
favour liver transplantation in advanced hepatic involvement of HHT.
518  Hepatology 2012
Disorders of the portal vein
In contrast to other disease entities affecting the hepatic vasculature, portal vein
thrombosis is a common disease. While portal vein thrombosis is located within the
main portal vein and its larger branches, rare forms of portal vein disease affecting
the medium-sized and preterminal portal venous branches have been identified. The
nomenclature for these diseases is inconsistent (e.g., obliterative portal venopathy,
hepatoportal sclerosis, idiopathic portal hypertension, nodular regenerative
hyperplasia).
Portal vein thrombosis
Portal vein thrombosis (PVT) is of heterogeneous aetiology. It is promoted by both
local and general risk factors (Tables 7 & 8). In about 20 to 30% of patients a local
risk factor can be identified. General risk factors are found in 50-70% (DeLeve
2009, Plessier 2010).
Table 7. Local risk factors for portal vein thrombosis.
Malignancy    •  Primary hepatic or abdominal cancer
•  Metastatic disease
Focal inflammation   •  Neonatal omphalitis, umbilical vein catheterisation
•  Pancreatitis, duodenal ulcer, cholecystitis
•  Diverticulitis, appendicitis, inflammatory bowel disease
•  Tuberculosis, CMV hepatitis
Portal venous injury   •  Cholecystectomy, splenectomy, colectomy, gastrectomy
•  Surgical portosystemic shunting, TIPS
•  Liver transplantation, hepatobiliary surgery
•  Abdominal trauma
Cirrhosis    •  Impaired hepatic inflow
Clinical presentation and diagnosis
Portal vein thrombosis may present as acute or chronic disease, representing
successive stages of the same disease. Special variants of PVT are malignant
thrombi resulting from tumours invading the portal venous circulation, septic
thrombi also known as acute pylephlebitis, and thrombi resulting from slowed portal
venous flow in liver cirrhosis (DeLeve 2009, Plessier 2010).
The typical clinical presentation of acute PVT includes abdominal or lumbar pain
of sudden onset or progressing over a few days. Depending on the extent of the
thrombosis the pain may be severe and colicky. The diminished mesenteric outflow
leads to intestinal congestion. Ileus may develop but without features of intestinal
obstruction. Moderate distension of the abdomen is common. However, peritoneal
signs are usually absent unless intestinal infarction develops. Fever and a marked
systemic inflammatory response may develop even without systemic infection. This
is accompanied by elevated laboratory markers of inflammation. In contrast, liver
function – apart from intermittent elevation of aminotransferases – is usually not
substantially affected by acute PVT unless significant liver damage pre-exists.
Clinical features should improve within 5-7 days. Otherwise transmural intestinal
ischemia has to be suspected.
Vascular Liver Disease  519
Pylephlebitis is characterized by high, spiking fever with chills, a painful liver,
and sometimes shock. Blood cultures should be taken (usually Bacteroides spp. ±
other enteric species). Infected thrombi give rise to the development of hepatic
microabscesses (Kanellopoulou 2010).
Cases in whom acute portal vein thrombosis does not resolve, progress to chronic
portal vein thrombosis. The obstructed portal vein is replaced by collateral veins
bridging the thrombotic part, known as portal cavernoma. There is wide variation in
the clinical picture of portal cavernoma. It may rarely lead to obstruction of the
extrahepatic bile ducts – so-called portal biliopathy which may be associated with
marked jaundice. However, the leading symptom of chronic PVT are the facets of
portal hypertension (e.g., portosystemic collaterals such as gastric or esophageal
varices). As liver function is usually not impaired, complications such as hepatic
encephalopathy or ascites are substantially less frequent than in liver cirrhosis.
Hepatopulmonary syndrome may be found in up to 10% of patients.
PVT is a common complication of liver cirrhosis with an increasing prevalence in
more severe disease stages. It needs to be discriminated from portal venous
obstruction caused by hepatocellular carcinoma. Pathophysiologically, PVT in
cirrhosis arises as a consequence of the reduction in hepatic inflow leading to flow
reduction and eventually stasis within the portal vein. Therefore, thrombi are often
partial and development of portal cavernoma is rather unusual. In patients with
cirrhosis, a newly developed ascites or significant worsening of existing ascites
should trigger the search for PVT.
Both acute PVT and portal cavernoma are easily detected using sonography, CT
or MR imaging. Acute PVT presents as intraluminal hyperechoic material in
ultrasound, while Doppler imaging demonstrates a lack of blood flow (Figure 3).
Using contrast-enhanced ultrasound (CEUS), vascularisation of the thrombus may
be used to identify malignant thrombi. As PVT may extend to the mesenteric or
splenic veins, thorough assessment of the splanchnic tributaries is mandatory. For
detailed assessment of thrombus extension, CT or MR angiography are more
sensitive than Doppler sonography. Portal cavernoma presents as serpiginous vessel
structures, while the main portal vein or its branches are not visible. As a
compensatory mechanism hepatic arteries are usually enlarged. Depending on the
individual location and appearance of portal cavernoma it may be mistaken as part
of the surrounding organs or as tumour.
Management and prognosis
In acute PVT, recanalisation of the obstructed veins should be aspired. Causal
factors require correction where possible. If pylephlebitis is suspected antibiotic
therapy should be commenced immediately.
Spontaneous recanalisation without anticoagulation occurs infrequently (<20%).
Therefore, anticoagulation is the most commonly used therapeutic strategy to
reopen the obstructed portal vein. Though no controlled studies exist, prospective
data suggest this approach to be successful in about 40% of patients. The success
rate increases to about 60% if neither the splenic vein is involved nor ascites is
detectable. Anticoagulation should be initiated as early as possible - delay might be
associated with treatment failure. Major complications are reported in less than 5%
of treated patients. (DeLeve 2009, Plessier 2010, Hall 2011).
Experience with other treatment modalities is limited (e.g., systemic/local
thrombolysis, surgical thrombectomy, transjugular intrahepatic portosystemic stent
520  Hepatology 2012
[TIPS]). Systemic thrombolysis appears largely ineffective. Although performed
successfully in some centres, major procedure-related complications and even death
have been reported for local thrombolysis, which has to be regarded as
experimental. Emergency surgical intervention is indicated in suspected intestinal
infarction. In these cases, surgical thrombectomy can be performed.
(A)
(B)
Figure 3. Acute portal vein thrombosis. Ultrasound of patient with acute PVT. (A)
Hyperechoic material is located within the main portal vein. (B) Using the power mode for flow
detection, blood flow is limited to those parts of the portal vein without hyperechoic material.
The therapeutic approach is different in patients with PVT associated with liver
cirrhosis. Interventional therapy using TIPS appears to be highly effective (Luca
Vascular Liver Disease  521
2011). Preliminary data even support the use of systemic thrombolysis in these
patients (De Santis 2010).
If treatment is initiated early in acute PVT the outcome is favourable. Symptoms
may sometimes disappear within hours after start of therapy and portal hypertension
rarely develops. Overall mortality is well below 10% (DeLeve 2009, Plessier 2010).
In patients with portal cavernoma prevention of gastrointestinal bleeding due to
portal hypertension is a main focus of therapy. The use of non-selective beta-blockers is incompletely evaluated in portal cavernoma. However, an approach
similar to portal hypertension in liver cirrhosis is supported by current guidelines
and appears to improve prognosis (DeLeve 2009). Due to the variable genesis of
PVT, individual assessment for risk of recurrence of thrombosis and risk of bleeding
should be performed. Although data is scarce, anticoagulation seems to be
favourable for most patients.
Nodular regenerative hyperplasia
Occlusion of the medium-sized and preterminal portal venous branches induces
hypotrophy of the supplied tissue. As a compensatory reaction, regeneration of
appropriately perfused tissue gives rise to the development of regenerative nodules.
This combination of hypotrophic and hypertrophic liver tissue without signs of
fibrosis is the equivalent of nodular regenerative hyperplasia (Wanless 1990).
Nodular regenerative hyperplasia causes 14-27% of cases with non-cirrhotic
portal hypertension (Naber 1991, Nakanuma 1996). In autopsy studies the
prevalence is 3.1/100,000, one third of which are associated with portal
hypertension (Colina 1989). Nodular regenerative hyperplasia is associated with
autoimmune and hematologic disorders, e.g., rheumatoid arthritis, Felty’s
syndrome, other connective tissue disorders and myeloproliferative disease. It has
also been described in infective endocarditis, in conjunction with chemotherapy and
after kidney transplantation (Matsumoto 2000).
Clinically, nodular regenerative hyperplasia presents with complications of portal
hypertension. Liver function is usually not significantly impaired although
individual cases with liver failure have been described (Naber 1990, Blendis 1978,
Dumortier 2001). The prognosis depends on the underlying disorder and on the
control of portal hypertension.
Hepatoportal sclerosis
Similar to nodular regenerative hyperplasia, hepatoportal sclerosis affects the
smaller portal venous branches. In contrast to the former, portal veins are not just
destroyed but replaced by filiform fibrotic strands penetrating the hepatic tissue.
These fibrotic strands are strictly confined to the portal tracts and do not form
fibrotic septae (Nakanuma 2001). Several synonyms are used for hepatoportal
sclerosis, e.g., obliterative portal venopathy or idiopathic portal hypertension.
However, nomenclature is not well-defined and sometimes overlaps with nodular
regenerative hyperplasia.
Hepatoportal sclerosis is rarely found in the Western world but is more common
in Asia (e.g., India, Japan). Several risk factors are in discussion: (a) chronic
infections, (b) exposure to medication / toxins (e.g., arsenic, vinyl chloride,
azathioprine), (c) thrombophilia, (d) immune disease and (e) hereditary factors.
Infections and toxins appear to be more common in Asia, while Western patients