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25. Alcoholic hepatitis
https://t.me/medicina_free
Liver transplantation
Alcoholic liver disease is still one of the most common indications
for liver transplantation in Europe and in the US (Burra 2005, European
Liver Transplant Registry 2011, Neuberger 1998, US Transplant Org 2011).
In guidelines for liver transplantation, patients need to have at least a
6-month period of alcohol abstinence before they can be evaluated for
transplantation, thus alcoholic hepatitis is usually a contraindication for
liver transplantation (Lucey 1997, Everhardt 1997, Lucey 2007).
A substantial number of patients with severe alcoholic hepatitis fail to
recover despite abstinence and medical therapy (Nakano 1982), and their
chances for spontaneous recovery may be poor (Worner 1985). The classical
opinion of European and North American experts considering acute
alcoholic hepatitis as a contraindication for transplantation (EASL 2012) has
recently been challenged by a case-control study showing an unequivocal
improvement of survival in patients who received early transplantation
(Mathurin 2011). Despite the fact that early liver transplantation for severe
alcoholic hepatitis may improve survival in those patients who fail medical
therapy, in many countries regulatory rules do not allow such transplants
without documentation of six months of abstinence. Future evaluation of
liver transplantation in carefully selected patients with severe alcoholic
hepatitis who do not respond to standard medical therapy may be supported
(Mathurin 2011).
Summary
Alcoholic hepatitis is a clinical diagnosis based on a history of heavy
alcohol consumption, jaundice, other signs of liver failure, and the absence
of other causes of hepatitis. A liver biopsy may be helpful but is not required
either to determine the diagnosis or prognosis. Abstinence from alcohol is
the prerequisite for recovery. Patients with signs of malnutrition should
have adequate nutritional support. Subjects with severe alcoholic hepatitis
(Maddrey’s discriminant function >32 or MELD score >21) who do not
have sepsis or other corticosteroid contraindications may receive 40 mg
prednisolone daily for 28 days (McCullough 1998, Lucey 2009). A treatment
algorithm based on current literature and EASL and US guidelines (O’Shea
2010, EASL 2012) is shown in Figure 6. Ater 7 days of corticosteroid
treatment, patients without obvious clinical beneit, without signiicant
improvement of jaundice and with a Lille score >0.45 may have disease that
will not respond to continued treatment with corticosteroids or an early
switch to pentoxifylline (Louvet 2008). In situations where administration of
corticosteroids appears to be risky, pentoxifylline may be tried (Lucey 2009,
O’Shea 2010, EASL 2012); this drug may decrease the risk of hepatorenal
syndrome that is oten lethal in alcoholic hepatitis. Patients with less severe
alcoholic hepatitis have a good short-term survival of >90% and should not
be treated with corticosteroids or pentoxyilline (Mathurin 2002).
Figure 6. Treatment algorithm in alcoholic hepatitis. The use of pentoxifylline has recently
been challenged by a large randomised trial (Thur z 2014); thus, its use is questionable
680 681
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Zhao XJ, Dong Q , Bindas J, et al. TRIF and IRF-3 bi nding to the TNF promoter results in macrop hage TNF dysregulation and steatos is induced
by chronic ethanol . J Immunol 2008;181:3049- 3056.
Zhou Z, Sun X , Kang YJ. Ethanol-induc ed apoptosis in mouse liver: Fa s- and cytochrome c-mediated ca spase-3 activation pathway. Am J Pathol
2001;159:329 -338.
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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.
Every single part of the hepatic vasculature may be afected, 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 signiicant disease
(Table 1).
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
•
• SP110-associated sinusoidal obstruction
syndrome
Congenital or acquired malformations • Webs, shunts, aneurysms
Acquired cellular defects •
Inflammatory disease, immunemediated disorders
Toxicity, radiation, trauma
Myeloproliferative neoplasms
•
Paroxysmal nocturnal hemoglobinuria
• Malignancy
•
Focal inflammatory lesions, e.g.,
pancreatitis, diverticulitis, appendicitis,
cholecystitis, abscesses, inflammatory
bowel disease
Vasculitis, e.g., polyarteritis nodosa,
•
Behçet’s disease
• Rheumatic disease
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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 ibrosis. Whether the latter represents a
separate disease entity is debatable, as perisinusoidal ibrosis is also
observed in common diseases such as steatohepatitis. Both sinusoidal
obstruction syndrome as well as peliosis hepatis are not strictly conined to
the hepatic sinusoids but may extend to the hepatic venous system.
Sinusoidal obstruction syndrome
(Hepatic veno-occlusive disease)
Sinusoidal obstruction syndrome (SOS), also referred to as hepatic
veno-occlusive disease (VOD), is a circulatory disorder primarily afecting
the hepatic sinusoids. Involvement of the hepatic central veins may occur,
but studies ater conditioning for hematopoietic cell transplantation have
demonstrated that in more than 40% of patients with SOS the hepatic
venous system is not involved. The proportion of sole sinusoidal afection
falls to 25% in patients with progression to severe SOS (DeLeve 2009).
Pathophysiology
Sinusoidal obstruction syndrome may be triggered by a variety of
factors (Valla 2016). By far the most common cause in the Western world
are myeloablative regimens in preparation for hematopoietic stem
cell transplantation (HSCTx), particularly when the transplant is for a
malignancy. Historically, the proportion of patients with SOS ater HSCTx
varied from the single-digit percentage range up to 50% if highly toxic
regimens were chosen. Currently, rates between 8% and 14% are reported
(Mohty 2015, Richardson 2013). 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). Among others
and in addition to the intensity of the chemotherapy applied, additional
risk factors appear to increase the risk for SOS: genetics, Karnofsky score,
exposure to estroprogestatives in women, autologous or allogeneic type of
HSCTx, prior myeloablative transplantation or preexistent liver disease
(DeLeve 2009, Mohty 2016).
Originally, the syndrome was described in conjunction with the
ingestion of herbal teas or foods containing pyrrolizidine alkaloids. Rarely,
SOS is caused by hereditary SP110 defects also leading to immunodeiciency
syndrome, VODI (Clife 2012). Whether immunodeiciency may give rise
to infections causing secondary SOS is under dedate. In addition, MTHF
mutations are suggested as a risk factor for SOS (Efrati 2014).
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 conirmed the primary sinusoidal damage infrequently
followed by central venous involvement (DeLeeve 1996, Mohty 2015). In
addition, chemotherapy might disturb sinusoidal repair by inhibiting
mobilisation of bone marrow progenitors of endothelial cells (Vion 2015).
Table 2. Conditions associated with sinusoidal obstruction syndrome
• Pyrrolizidine alkaloid-containing
herbs, e.g. comfrey, groundsel,
rattlebox, traditional Chinese
medicine preparations
Radiation exposure
•
•
Pregnancy
DRUGS
• 6-mercaptopurine
• 6-thioguanine
• Actinomycin D (Dactinomycin)
• Azathioprine**
•
Busulfan*
• Cytosine arabinoside
• Cyclophosphamide*
• Dacarbazine
• Doxorubicin (Adriamycin)
*Exclusively reported with conditioning regimens for HSCTx
**Reports for azathioprine-associated SOS included concurrent potential causes of SOS
(modified according to DeLeve 2009, Thatishetty 2013, Tewari 2017)
• Hereditary SP110 defects
• MTHFR mutations
• ABCB11 mutations
•
Gemtuzumab ozogamicin
• Irinotecan
• Melphalan*
• Mitomycin
•
Oxaliplatin, Carboplatin
• Urethane
• Vinblastine
• Sirolimus
• Isavuconazole
Clinical presentation and diagnosis
SOS characteristically presents with 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 ater
cyclophosphamide-containing regimens but can be delayed up to 1 month
ater conditioning therapy if other therapies are used.
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 (Dignan 2013, Bajwa 2017). In patients meeting these criteria,
diagnosis can be made with reasonable certainty and solely based on
clinical judgement. Diferential diagnoses comprise cholestatic jaundice
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due to sepsis, drug-induced cholestasis, luid overload due to renal failure
or congestive heart failure, liver involvement by viral or fungal infections,
and acute grat-versus-host disease.
However, in up to 20% of patients the diagnosis of SOS cannot reliably
be 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). Measurement of various biomarkers was suggested
as indicator and follow-up marker of SOS (e.g. von Willebrand factor,
thrombomodulin, E-selectin, sICAM1, PAI-1). Their use, however, is still
regarded as experimental (Dignan 2013, Bajwa 2017). In 2016 the European
Society for Blood and Marrow Transplantation revised the criteria for
diagnosis and severity (Table 4). Taking into account that the paediatric
population signiicantly difers from adults, separate criteria were recently
established for children (Corbacioglu 2018).
Table 3. Diagnosis of sinusoidal obstruction syndrome af ter 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
•
Hyperbilirubinaemia >34.2 µmol/L
(2 mg/dL) plus ≥2 additional criteria
•
Usually painful hepatomegaly
• ≥5% weight gain
• Ascites
The gold standard to conirm SOS is based on the combination of hepatic
histology plus measurement of the wedged hepatic venous pressure gradient
(HVPG >10 mmHg, speciicity >90%, PPV >85%). Both can be achieved
during a single procedure via the transvenous route, especially as increased
bleeding risk oten precludes percutaneous liver biopsy. However, histology
may be negative due to the sometimes patchy character of the disease.
Imaging techniques are used to conirm hepatomegaly or ascites and will
help to rule out diferential diagnoses such as biliary obstruction. A more
speciic sign is the inding of hepatic inlow blockage with re duced or reversed
portal low in colour Doppler ultrasound (Figure 1). In addition, attenuation
of hepatic venous low or gallbladder wall edema may be detected. Some
authors suggest the use of composite ultrasound imaging scores (Lassau
2002). Though less speciic, CT imaging (i.e. heterogeneous hypoattenuation
and patchy enhancement in the portal venous or equilibrium phase) may be
suggestive for SOS (Yang 2018).
*The 20-day rule applies to cyclophosphamide-containing regimens and should be adjusted
according to the regimen actually used
Table 4. Revised EBMT criteria for diagnosis of sinusoidal obstruction syndrome in adults*
(Mohty 2016)
Classical SOS
In the first 21 days after HSCT
Bilirubin >34 μmol/L (2 mg/dL) and two
of the following criteria must be present:
• Painful hepatomegaly
• Weight gain >5%
•
Ascites
*Symptoms/signs should not be attributable to other causes
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Late onset SOS
>21 Days after HSCT
• Classical SOS beyond day 21
OR
• Histologically proven SOS
OR
Two or more of the following criteria:
•
– Bilirubin >34 μmol/L (2 mg/dL)
– Painful hepatomegaly
– Weight gain >5%
– Ascites
AND
•
Hemodynamical +/– ultrasound
evidence of SOS
Figure 1. Doppler ultrasound in sinusoidal obstruction syndrome. Exemplary case showing
undulating portal venous flow in a jaundiced patient after HSCTx
Severity of SOS varies from mild forms to rapidly progressing and
eventually life-threatening disease (McDonald 1993). In patients without
need for treatment of luid excess or hepatic pain, SOS is considered mild
and is associated with a self-limited course. Treatment associated with a
complete remission within 100 days is considered moderate disease. If SOS
does not resolve by day 100, it is categorised as severe. This classiication,
however, is retrospective and does not support clinical decision-making.
The EBMT has proposed a modiied classiication system (Mohty 2016)
(Table 5).
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Table 5. EBMT criteria for severity of sinusoidal obstruction syndrome in adults (Mohty 2016)
Milda Moderate
Time since first
clinical symptoms
c
of SOS
Bilirubin (μmol/L) ≥34 and <51 ≥51 and <85 ≥85 and <136 ≥136
Bilirubin kinetics Doubling
Transaminases ≤2 x normal >2 and ≤5 x
Weight increase <5% ≥5% and <10% ≥5% and <10% ≥10%
Renal function <1.2 x
a
In two or more risk factors for SOS, patients should be in the upper grade
b
Multi-organ dysfunction must be classified as ver y severe
c
Time between first signs/symptoms and fulfillment of SOS diagnostic criteria
>7 D a y s 5 –7 D a y s ≤4 Days Any time
normal
≥1.2 and <1.5
baseline at
transplant
x baseline at
transplant
a
Severe Very severe
within 48 h
>5 and ≤8 x
normal
≥1.5 and <2
x baseline at
transplant
>8 x normal
≥2 x baseline at
transplant or signs
of MOD/MOF
b
Management and prognosis
Taking into account that SOS is probably under-diagnosed by 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 complications leading to multiple organ failure (renal,
pulmonary) are the main reasons for death in these patients (Mohty 2015).
This underlines the necessity of a closely supervised management concept.
Highly toxic conditioning regimens should possibly be avoided. Recently,
SOS prophylaxis using ursodeoxycholic acid was recommended (Cheuk
2015). In high-risk patients, deibrotide may be used (Dignan 2013, Mohty
2015).
Several treatments have been suggested for established SOS, e.g.,
thrombolysis using tPA, deibrotide or methylprednisolone (DeLeve 2009,
Dignan 2013, Richardson 2013). In addition, invasive strategies such as TIPS
or liver transplantation have been evaluated. Primarily, luid management
should aim to control luid overload (using diuretics, paracentesis,
hemoiltration/hemodialysis) and adequate oxygenation should be provided
(Mahadeo 2017, Ovchinsky 2018). Thrombolysis has not proved successful
and was associated with severe complications. Deibrotide, a mixture of
single-stranded oligodeoxyribonucleotides derived from porcine intestinal
mucosa, works as an endothelial protective agent (Palomo 2016). Deibrotide
was successfully tested in phase II and III trials both in paediatric and
adult settings (Richardson 2010, Corbacioglu 2012, Richardson 2016). This
compound can also be used in multiple organ failure without substantially
increasing the bleeding risk. However, current data support deibrotide
use as soon as SOS is diagnosed. Methylprednisolone may be considered as
additional therapy (Dignan 2013).
Unlike Budd-Chiari syndrome, decompression of portal hypertension
using TIPS does not improve SOS. For patients with favourable prognosis of
the underlying hematopoietic disorder ater HSCTx, liver transplant might
possibly be considered.
Peliosis hepatis
Peliosis hepatis is a rare and potentially reversible disorder characterised
by single or multiple blood-illed cystic cavities within the hepatic tissue.
Whether it is related to nonobstructive sinusoidal dilatation is currently
unclear (Marzano 2015). Prevalence of peliosis hepatis may vary between
0.03% in HIV infection, 0.2% in pulmonary tuberculosis and up to 20%
ater renal transplantation. There is no favoured localisation of the peliotic
lesions. It may occur at all ages, including a fetal form. The size ranges from
submillimetr es to cent imetres but rarely exceeds 3 cm. The histopathological
appearance may show a missing endothelial cell lining with hepatocytes
directly serving as boundary (parenchymal type). Alternatively, the
endothelium may be preserved but the hepatic sinusoids appear dilated.
The aneurysmal dilation may extend to the central vein (phlebectatic type)
(Yanof 1964, Tsokos 2005).
Pathophysiology
Several risk factors have been suggested as promoters of peliosis hepatis,
e.g., infections, drugs or malignant disorders (Table 6). However, the exact
pathogenesis of peliosis is still unclear. Histology suggests endothelial
damage leading to 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 bloodilled 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.
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Table 6. 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
Inflammatory
disease
Miscellaneous • Renal or heart transplantation
Multiple myeloma, Waldenström disease
•
•
Hodgkin disease
•
Hepatocellular adenoma
Celiac disease
•
•
Systemic lupus erythematodes
• Diabetes mellitus
• Hereditary hemorrhagic telangiectasia
• Pregnancy
•
No underlying disorder in up to 50%
Clinical presentation and diagnosis
Peliosis hepatis is mostly asymptomatic and incidentally detected
by hepatic imaging. Rarely, the peliotic cysts may rupture leading to
intrahepatic or intraabdominal hemorrhage. Individual cases with overt
liver disease have been 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 the lungs, kidneys, parathyroid or
adrenal glands, or other parts of the gastrointestinal tract.
Usually, peliosis hepatis is easily detected by imaging techniques
(Ronot 2016). However, discrimination between peliosis and other benign
or malignant lesions may turn diicult. Peliotic lesions miss a mass efect
on the adjacent hepatic vasculature. Blood low within the lesion is slow,
resulting in a hypodense appearance ater 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 (Iannaccone 2006). In contrastenhanced ultrasound (CEUS) both centrifugal as well centripetal contrast
illing might be detected, in some cases even tumour-like behaviour occurs
(Schuldes 2011). Though imaging techniques may assist the diagnosis
of peliosis hepatis, a liver biopsy is oten needed for inal conirmation.
Wedged hepatic venography may also be diagnostic, but its use needs strong
suspicion.
Management and prognosis
Typically, peliosis hepatis will not progress to symptomatic disease.
In these patients management has to concentrate on the identiication
and, if required, treatment of the underlying disease. Causal treatment
is the therapeutic mainstay mostly leading to regression of the peliotic
lesions. Individual cases may require surgery if the risk of cyst rupture
and consecutive bleeding is estimated to be high. If liver failure or portal
hypertension dominate the clinical picture liver transplantation might be
considered provided aetiology does not pose a contraindication.
Disorders of the hepatic artery
Pathologies involving the hepatic artery may lead to diferent clinical
pictures (Table 7, Figure 2).
Occlusion of the arterial lumen results in ischaemia of the supplied
tissue. Though gross hepatocellular necrosis may follow, such as in ischemic
hepatitis, preserved portal venous oxygen supply oten prevents the most
devastating damage. In 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 cholestasisassociated liver enzymes (i.e., gamma GT, alkaline phosphatase). In more
severe cases, structural damage to bile ducts may be irreversible (i.e.,
ischemic cholangiopathy). Especially ater orthotopic liver transplantation
ischaemia type biliary lesions (ITBL) still pose a major challenge for clinical
management.
Table 7. Aetiology of hepatic ar tery disease
Obstruction or
destruction of the
hepatic artery
Aneurysms • Congenital malformations
Shunts • Congenital malformations
• Hepatic artery embolism or thrombosis
• Vasculitis
•
Sickle cell disease
• Thrombotic microangiopathy (e.g., hemolytic uremic syndrome,
thrombotic thrombocytopenic purpura, HELLP syndrome)
• Chronic transplant rejection
• Trauma
•
Polyarteritis nodosa (PAN)
• Focal inflammation, trauma
• Hereditary hemorrhagic teleangiectasia
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Apart from sequelae due to hepatic ischaemia, hepatic artery disease
may present either as an aneurysm or as a shunt. Aneurysms of the hepatic
artery are oten detected incidentally by imaging. In the majority, they are
asymptomatic but abdominal pain or – in rare cases – obstructive jaundice
may develop. In about 20% of cases multiple aneurysms are present. Males
are more oten afected 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 individualised including radiological
interventions or surgical procedures.
Figure 2. Spontaneous arteriopor tal shunt. Angiography in a patient with non-cirrhotic por tal
hypertension. A small arterioportal shunt is detected by superselective catheterisation
Hereditary hemorrhagic telangiectasia
(Osler-Weber-Rendu syndrome)
Hereditary hemorrhagic telangiectasia (HHT) is a highly penetrant,
autosomal dominant disease showing a heterozygous prevalence between
1:5,000 and 1:8,000. It is characterised by progressive and multivisceral
development of arteriovenous malformations (Govani 2009, Garg 2014,
Ar thur 2015).
Mutations in several genes interacting with transforming growth factor
(TGF)-β receptor have been identiied in HHT. According to the genes
involved, diferent 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 identiied, chromosome 5q31.3-q32),
• HHT 4 (gene not yet identiied, chromosome 7p14),
• HHT 5 (HHT5 coding for GDF-2, also known as BMP-9, chromosome
10q11.22),
• 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 characterised by marked
intrafamilial variation. Recently, the irst case of tissue-speciic mosaicism
was reported (McDonald 2018).
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., anaemia, seizures, subarachnoid hemorrhage,
paraplegia, transient ischemic attacks/stroke, dyspnea, cyanosis,
polycythaemia, 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. Thereater it takes one or
two decades for the development of signiicant bleeding or symptomatic
visceral involvement (Plauchu 1989, Govani 2009, Arthur 2015). Overall, life
expectancy of patients sufering from HHT is two decades less than in the
general population (Droege 2018).
The proportion of hepatic involvement in HHT reaches up to 75%. Hepatic
malformations appear more common in females. However, less than 20%
of patients with hepatic involvement are symptomatic (Singh 2014). 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 sufer from high output
cardiac failure. In addition, symptoms of a mesenteric steal syndrome
(e.g., postprandial abdominal pain) and complications of biliary ischaemia
(e.g., biliary abscesses) may occur. As a consequence of ischaemia, nodular
regeneration of the liver develops (HHT-associated pseudocirrhosis).
Arterioportal malformations will cause portal hypertension (Buscarini
2006, Garcia-Tsao 2000).
Diagnosis of HHT is made using the Curaçao criteria, 3 of 4 of which
need to be fulilled (Shovlin 2000, Faughnan 2011):
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• recurrent spontaneous epistaxis,
• telangiectasias, multiple and in typical localisation,
• positive family history,
• visceral arteriovenous malformations (lung, liver, brain, spine).
Table 8. Ultrasound criteria for hepatic involvement in HHT*
Major criteria • Dilated common hepatic artery >7 mm (inner diameter)
Intrahepatic arterial hypervascularisation
•
Minor criteria • V
Facultative findings • Dilated portal vein >13 mm
*Two major criteria: definitive hepatic involvement in HHT, one major criterion plus minor
criteria: probable hepatic involvement (modified according to Caselitz 2003)
of the proper hepatic artery >110 cm/s
max
•
RI of the proper hepatic arter y <0.60
of the portal vein >25 cm/s
• V
max
• Tortuous course of the extrahepatic hepatic artery
•
Dilated liver veins >11 mm
• Hepatomegaly >15 cm in midclavicular line
• Nodular liver margin
Current guidelines do not endorse routine screening for hepatic
vascular malformations. Recently, a diagnostic score involving age, gender,
hemoglobin and alkaline phosphatase was presented to identify patients
at risk for signiicant liver disease (Singh 2014). However, using Doppler
ultrasound, screening is performed with high sensitivity and speciicity
(Table 8) (Caselitz 2003). If hepatic involvement is conirmed, cardiac output
should be estimated (e.g., via echocardiography). Furthermore, screening at
regular intervals is advised to detect complications such as development of
portal hypertension or biliary lesions.
bevacizumab was helpful in treating vascular malformations (Buscarini
2019). Single cases using kinase inhibition (i.e., sunitinib, nintedanib) were
reported, but still have to be regarded experimental.
Limited data exist for the use of hepatic artery embolisation and liver
transplantation (Buscarini 2006, Chavan 2013, Felli 2017). Due to the
invasiveness and complication rates of these approaches only patients
with moderate to severe symptoms should be regarded as candidates
for interventional therapy. Hepatic artery embolisation can be used to
reduce shunt low in patients with arteriovenous hepatic shunts leading
to signiicant reduction of cardiac output and improvement of associated
symptoms. 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 experienced
centres but do favour liver transplantation in advanced hepatic involvement
of HHT.
Disorders of the portal vein
Portal vein thrombosis is a common disease located within the main
portal vein and its larger branches. Additionally, rare afections of the
medium-sized and preterminal portal vein branches have been identiied.
The nomenclature for the latter has been inconsistent (e.g., obliterative
portal venopathy, hepatoportal sclerosis, idiopathic portal hypertension,
nodular regenerative hyperplasia). Recently, the term idiopathic noncirrhotic portal hypertension was established replacing and incorporating
the diferent previously decribed subtypes (EASL 2016).
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,
danocrine), antiibrinolytics (aminocaproic acid, tranexamic acid) and other
experimental drugs (tamoxifen, interferon, thalidomide, sirolimus) were
suggested (Ardelean 2015, Faughnan 2011). However, no data supports the
use of these drugs to treat hepatic vascular malformations. A phase 2 trial
evaluated bevacizumab to treat liver involvement in HHT (Dupuis-Girod
2012). Signiicant improvements in cardiac output, epistaxis and SF-36
scores were achieved. However, long-term efects, dosing and necessity of
maintenance therapy are still unclear (Ardelean 2015, Chavan 2017). Registry
data comparing thalidomide and bevacizumab show positive efects on
transfusion dependency, GI bleeding and epistaxis for both drugs while only
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Portal vein thrombosis
Portal vein thrombosis (PVT) is the most frequent disorder afecting the
hepatic vasculature. Autopsy studies report a prevalence range between
0.05% and 0.5%. In compensated cirrhosis PVT may be found in 1% of cases,
while prevalence between 8% and 26% are reported for decompensated
cirrhosis.
PVT is of heterogeneous aetiology. It is promoted by both local and
systemic risk factors (Tables 9 & 10). In about 20 to 30% of patients a local
risk factor can be identiied. Systemic risk factors are found in 50-70%
(DeLeve 2009, Plessier 2010). Recently, central obesity was identiied as a
major risk factor for idiopathic PVT (Bureau 2016).
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