Book on hepatitis from page 522 to 531

Book on hepatitis from page 522 to 531

522  Hepatology 2012
suffer more often from thrombophilia (Schouten 2011). Also, HIV infection is
regarded as a risk factor for hepatoportal sclerosis.
Liver function as well as liver enzymes are usually unaffected by hepatoportal
sclerosis. Complications of portal hypertension pose the main clinical challenge.
Typically, the long-term clinical course of the disease is rather stable. Similarly to
nodular regenerative hyperplasia, prognosis depends on the underlying disorder and
on the control of portal hypertension (Schouten 2011).
Disorders of the hepatic veins
Budd-Chiari syndrome is the only defined entity of hepatic venous disease.
However, other disorders such as the sinusoidal obstruction syndrome or peliosis
hepatis may also affect the hepatic venous system. Furthermore, hepatic congestion
due to cardiac or pericardial disease shares clinical similarities with Budd-Chiari
syndrome.
Budd-Chiari syndrome
Budd-Chiari syndrome (BCS) is defined as hepatic venous outflow obstruction at
any level from the small hepatic veins to the junction of the inferior vena cava
(IVC) and the right atrium, regardless of the cause of obstruction (Janssen 2003).
Excluded from this definition are obstructions caused by sinusoidal obstruction
syndrome and cardiac or pericardial disorders.
Pathophysiology
Obstruction of the hepatic outflow may arise from endoluminal lesions, e.g.,
thrombosis, webs, endophlebitis (primary BCS) or from outside the venous system
by luminal invasion or by extrinsic compression, e.g., tumour, abscess, cysts
(secondary BCS) (Janssen 2003).
On rare occasions, BCS originates from congenital malformations, e.g., webs or
stenotic vessels (Ciesek 2010, Darwish Murad 2009). However, outflow obstruction
is usually caused by thrombosis. Prevalence of thrombophilic risk factors are given
in Table 8. Thrombi are exclusively located within the hepatic veins in 49% of
patients, exclusively within IVC in 2%, and as combined thrombosis of hepatic
veins and IVC in 49%. In about 18% a concomitant portal vein thrombosis is
identified (Darwish Murad 2009).
Obstruction of hepatic outflow leads to congestion of the drained tissue. Over
time this will induce hypotrophy of affected and consecutive regeneration of non-affected parts of the liver. A typical area of hypertrophy is liver segment 1 (caudate
lobe), because it possesses its own separate venous drainage into the IVC.
Regenerative nodules may occasionally progress to hepatocellular carcinoma. In
addition, intrahepatic collaterals may develop.
Clinical presentation and diagnosis
Depending on the location of outflow obstruction, the number of vessels involved
and the temporal dynamics of BCS, the clinical presentation varies between light
symptoms, even sometimes subclinical disease and dramatic acute complaints
which may progress to acute liver failure. The disease might present with a
progressively relapsing course successively involving different hepatic veins.
Symptoms of hepatic congestion are ascites (>80% of patients), abdominal pain
(>60%) and esophageal varices (>50%). Disturbance of liver function is rather rare,
Vascular Liver Disease  523
e.g., hepatic encephalopathy (<10%), as is involvement of extrahepatic organs, e.g.,
hepatorenal syndrome (<10%) (Darwish Murad 2009).
In the majority of cases, diagnosis of BCS can be obtained using Doppler
ultrasound. If technical difficulties obviate diagnosis by ultrasound, MRI is the
imaging method of choice. Only in rare cases, liver biopsy or hepatic venography
are required to confirm the diagnosis (Janssen 2003). Ultrasound characteristics of
BCS are clearly defined (Boozari 2008). They comprise specific signs such as direct
visualisation of thrombi, stenoses, webs, replacement of hepatic veins by fibrotic
strands or reversed flow in hepatic veins or IVC. Suggestive signs are hepatic
collaterals that may be interposed between hepatic veins or may be located on the
hepatic capsula. Widening of the caudate vein (>3 mm) is also regarded as
suggestive for BCS. These signs serve in the diagnosis of BCS and may be
accompanied by a myriad of non-specific changes (e.g., ascites, regenerative
nodules, splenomegaly).
Table 8. Prevalence of thrombophilic risk factors in acute and chronic portal vein
thrombosis and in primary Budd-Chiari syndrome*.
Risk factor  Portal vein
thrombosis
Budd-Chiari
syndrome
Myeloproliferative disorders
Atypical
Classical
21% - 40%
14%
17%
40% - 50%
25% - 35%
10% - 25%
Paroxysmal nocturnal hemoglobinuria  0% - 2%  0% - 19%
Antiphospholipid syndrome   6% - 19%  4% - 25%
Factor V Leiden mutation  3% - 32%  6% - 32%
Factor II (prothrombin) mutation  14% - 40%  3% - 7%
Protein C deficiency  0% - 26%  4% - 30%
Protein S deficiency  2% - 30%  3% - 20%
Antithrombin deficiency  0% - 26%  0% - 23%
Plasminogen deficiency  0% - 6%  0% - 4%
Hyperhomocysteinemia
TT677 MTHFR genotype
11% - 22%
11% - 50%
22% - 37%
12% - 22%
Recent pregnancy  6% - 40%  6% - 12%
Recent oral contraceptive use  12% - 44%  6% - 60%
Behçet’s disease  0% - 31%  0% - 33%
Connective tissue disease  4%  10%
* Adult patients without malignancy or cirrhosis (according to DeLeve 2009, Darwish Murad
2009, Plessier 2010).
Management and prognosis
Treatment strategy in BCS has to be adjusted to the etiology of BCS and the
severity of the clinical picture. If BCS is caused by congenital malformations such
as webs, radiological interventions using balloon catheter-assisted dilation may be
sufficient to solve the problem.
In case of a primary thrombotic event, anticoagulation is the mainstay of therapy
(Janssen 2003, DeLeve 2009, Darwish Murad 2009). However, in medium-term
follow-up less than one third of patients will be solely treated with anticoagulation
524  Hepatology 2012
and remain free of further interventions (Darwish Murad 2009). Therefore,
interventional techniques (e.g., TIPS, recanalisation) should be evaluated early,
especially in patients with moderate to severe symptoms. With the advent of TIPS,
the necessity for liver transplantation in BCS has declined sharply. Success rates of
TIPS – both in the short-term and in the long-term – are high. Thus, surgical
procedures (e.g., surgical shunt, liver transplantation) are only rarely performed.
With this approach, actual data show that survival in BCS is above 80% after 2
years (Darwish Murad 2009).
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526  Hepatology 2012
30. Acute Liver Failure
Akif Altinbas, Lars P. Bechmann, Hikmet Akkiz, Guido Gerken, Ali Canbay
Introduction and definition
Acute liver failure (ALF) is a devastating clinical syndrome, occurring in previously
healthy individuals, which is characterized by hepatocellular death and dysfunction
(O'Grady 2005). ALF is characterized by onset of coagulopathy (International
Normalized Ratio, INR ≥1.5) and hepatic encephalopathy within 26 weeks of
symptom appearance in a previously healthy subject (Larson 2010). Exclusion of an
underlying liver disease (alcoholic hepatitis, chronic HBV and HCV, autoimmune
hepatitis) is mandatory, as management of acute-on-chronic liver failure differs
from ALF treatment. The most common causes of ALF in Europe and the US are
acetaminophen  intoxication, acute hepatitis B (HBV) infection and non-acetaminophen drug-induced liver injury (Bernal 2010). With progressive loss of
hepatic function, ALF leads to hepatic encephalopathy, coagulopathy, and
multiorgan failure within a short period of time. Established specific therapy
regimens and the introduction of liver transplantation (LTx) improves the prognosis
for some etiologies. However, the overall mortality rate remains high (Bernal 2010).
ALF accounts for approximately six to eight percent of LTx procedures in the US
and Europe (Lee 2008). The accurate and timely diagnosis of ALF, rapid
identification of the underlying cause, transfer of the patient to a specialised
transplant center and, if applicable, initiation of a specific therapy and evaluation for
LTx are crucial for modern ALF management. Therefore, we focus here on
epidemiology, pathophysiology, diagnosis and treatment of ALF, including a brief
overview of different etiologies and specific treatment options as well as novel tools
to predict prognosis.
Epidemiology and etiologies
ALF is a rare disease based on multiple causes and varying clinical courses, and
exact epidemiologic data is scarce. The overall incidence of ALF is assumed as one
to six cases per million people each year (Bernal 2010). Recent data from the US
(Ostapowicz 2002), the UK (Bernal 2004), Sweden (Wei 2007), and Germany
(Canbay 2009) reveal drug toxicity as the main cause of ALF, followed by viral
hepatitis followed by unknown etiology. In contrast, in the Mediterranean, Asia, and
Acute Liver Failure  527
Africa, viral hepatitis is the main cause of ALF (Escorsell 2007, Koskinas 2008,
Mudawi 2007, Oketani 2011).
Table 1. Etiologies of ALF.
Intoxication  Direct, idiosyncratic, paracetamol, ecstasy, amanita, phenprocoumon,
tetracycline, halothane, isoniazid, anabolic drugs
Viral hepatitis  HBV, HAV, HEV, HBV+HDV, CMV, EBV, HSV
Immunological  Autoimmune, GVHD
Metabolic  Wilson’s disease, alpha 1 antitrypsin deficiency, hemacromatosis
Vascular  Budd-Chiari syndrome, ischemic, venoocclusive disease
Pregnancy-induced  HELLP syndrome
Intoxication
Drug-induced liver injury
Drug toxicity is the main cause of ALF in Western societies. Although the incidence
of drug-induced liver injury (DILI) in the general population was estimated at 1-2
cases per 100,000 person years (de Abajo 2004), in Germany DILI accounts for
approximately 40% of patients with ALF (Canbay 2009). As a structured medical
history may be difficult in some cases, a standardised clinical management to
identify the cause of DILI and optimize specific treatment has been proposed
(Fontana 2010). This includes assessment of clinical and laboratory features,
determining the type of liver injury (hepatocellular vs. cholestatic), the clinical
course after cessation of the suspected drug, assessment of risk factors (age, sex,
alcohol consumption, obesity), exclusion of underlying liver diseases, previous
episodes of DILI, liver biopsy and in some cases rechallenge to identify the drug.
Furthermore, to identify a cause, one must distinguish between a direct (intrinsic;
dose-dependent) and an idiosyncratic (immune-mediated hypersensitivity or
metabolic injury) type of liver injury (Larson 2010). Acetaminophen intoxication, as
discussed in detail below, is the prototype of a direct, dose-dependant intoxication
with acute hepatocellular necrosis. However, most cases of DILI are due to
idiosyncratic reactions with a latency period of up to one year after initiation of
treatment. Drugs that induce idiosyncratic DILI include narcotics (halothane),
antibiotics (amoxicilline/clavulanate; macrolides, nitrofurantoine, isoniazid),
antihypertensive drugs (methyldopa) and anticonvulsants and antipsychotic drugs
(valproic acid, chlorpromazine) and many others, including herbal medicine.
Demonstrating the need for new algorithms and biomarkers of liver injury, the
observation by Hy Zimmerman, that elevation of transaminase levels above three
times the upper limit of normal indicates early DILI, is still in use to assess the risk
of DILI in drugs in development since the 1970s (Reuben 2004).
Acetaminophen intoxication
In a recent study, more than seventy percent of the patients with acetaminophen-induced ALF were reported as suicidal intents, the rest as accidents (Canbay 2009).
The presence of any ALF risk in the recommended dose range of acetaminophen is
controversial. However, the presence of risk factors, particularly obesity and alcohol
abuse seem to increase the risk of ALF in patients that use acetaminophen (Canbay
2005, Krahenbuhl 2007). Acetaminophen serum concentrations above 300 μg/mL
four hours after the ingestion is a predictor for severe hepatic necrosis. With high
528  Hepatology 2012
doses of acetaminophen its metabolite N-acetyl-p-benzoquinone imine (NAPQI)
accumulates in hepatocytes and induces hepatocellular necrosis. In the presence of
glutathione, NAPQI is rapidly metabolized to non-toxic products and excreted via
the bile (Bessems 2001). In acetaminophen intoxication, the glutathione pool is
rapidly diminished, but could easily be restored by N-acetylcysteine therapy (see
below).
Table 2. Clinical determination of the cause of ALF.
Etiology  Subtype  Investigation
Intoxication  Drug  Drug concentrations in serum
Amanita  History
Idiosyncratic drug toxicity  Drug concentrations in serum/
eosinophil count
Viral hepatitis  HAV  IgM HAV
HBV  HBsAg, IgM anti-core, HBV DNA
HBV/HDV  IHBsAg, gM HDV, HDV RNA
HCV  Anti-HCV, HCV RNA
HEV  Anti-HEV
Immunological  Autoimmune  ANA, LKM, SLA, ASMA, IgG
GVHD  Biopsy
Metabolic  Wilson’s disease  Urinary copper, coeruloplasmin in
serum, slit-lamp examination
AT deficiency  AT level in serum, AT genotyping
Hemacromatosis  Ferritin in serum, transferrin
saturation
Vascular  Budd-Chiari syndrome  Ultrasound (Doppler)
Ischemic  Ultrasound (Doppler),
echocardiography (ECO)
Veno-occlusive disease  Ultrasound (Doppler)
Pregnancy-induced  HELLP syndrome  Hematocrit test, peripheral blood
smear, platelet count
N/A, not available; ANA, anti-nuclear antibody; ASMA, anti-smooth muscle antibody; IgM,
immunoglobulin M; IgG, immunoglobulin G; HBsAg, hepatitis B surface antigen.
Amanita intoxication
The spectrum of mushroom poisoning varies from acute gastroenteritis to ALF.
Even though the mortality rate of all mushroom  poisoning cases is low, the
mortality rate of those patients who develop ALF is extremely high, despite the
improvement in intensive care management (Broussard 2001). Amanita phalloides,
the wild mushroom, is attributed to the deadly mushroom poisoning, which occurs
mostly in spring and early summer. Amanita toxin has a dose-dependant, direct
hepatotoxic effect and distrupts hepatocyte mRNA synthesis (Kaufmann 2007).
Acute Liver Failure  529
Viral hepatitis
Historically the most common cause of ALF in Europe and nowadays still the most
prevalent etiologies in developing countries is fulminant viral hepatitis (Larson
2010). Hepatitis A and E (HAV and HEV), both transmitted via the fecal-oral route
are endemic in countries with poor sanitation, tropical and subtropical countries.
HEV was determined as the main cause of ALF in some Asian countries. The
clinical presentation of HAV is more severe in adults than in children, and HEV is
more common in pregnant women, especially in the third trimester (Dalton 2008).
Fulminant HBV, transmitted vertically or by infected blood and body fluids is the
most predominant viral cause of ALF in Western countries (Bernal 2010, Canbay
2009). The incidence of fulminant HBV is decreasing with the implementation of
routine vaccination. Super-infection with hepatitis D virus in HBV infection is
associated with higher risk to develop ALF. HBV infection and treatment is
discussed in detail elsewhere. Acute cytomegalovirus, Epstein-Barr virus,
parvovirus B19, and herpes simplex virus type 1 and 2 are less frequently associated
with ALF.
Immunologic etiologies
Autoimmune hepatitis
In rare cases autoimmune hepatitis (AIH) may induce ALF. The acute onset of ALF
and its potentially rapid progression causes a diagnostic dilemma since exclusion of
other liver diseases might be too time-consuming in patients with ALF secondary to
AIH. Thus, IgG elevation and positive ANA titer, combined with typical
histological features might be sufficient to induce specific therapy in this cohort
(Suzuki 2011). However, as DILI might perfectly mimic AIH, detailed history
taking is the key to adequate therapy in all ALF patients with features of AIH
(Bjornsson 2010).
Graft versus host disease
With the development of new options of donor leukocyte infusion, non-myeloablative methods and umbilical cord blood transplantation, the indications of
allogenic hematopoietic stem cell transplantation have been expanding in recent
years (Ferrara 2009). Therefore, any hepatopathy in patients who have undergone
bone marrow transplant is suspicious for Graft versus Host Disease (GVHD). On
the other hand, chemotherapy and myeloablation themselves are hepatotoxic and
might induce reactivation of HBV infection, leading to fulminant liver failure.
Wilson’s Disease
Wilson’s Disease (WD), the autosomal recessive disorder of copper metabolism, is
a rare cause of ALF. The prognosis of WD patients presenting with ALF is
devastating, and almost all die without LTx (Lee 2008). Very high serum bilirubin
and low alkaline phosphatase are typical laboratory constellations, and renal failure
is a common clinical feature in WD.
Vascular disorders
Acute systemic hypotension secondary to heart failure or systemic shock syndromes
may induce acute liver injury (Canbay 2009). Occlusion of at least two liver veins in
Budd-Chiari syndrome or venoocclusive disease is a rare cause of ALF.
Anticoagulatory or lysis therapy is the management of choice; in severe cases,
530  Hepatology 2012
emergency TIPSS or surgical shunt placement may be indicated, as well as a
thorough workup to identify any underlying prothrombotic conditions (Fox 2011).
Pregnancy-induced liver injury
Besides acute fatty liver of pregnancy (AFLP), which usually occurs in the third
trimester of pregnancy, HELLP syndrome (hemolysis, elevated liver enzymes, low
platelet level) is a rare complication of pregnancy and presents with ALF. HELLP
syndrome typically presents with LDH, ALT and bilirubin elevation and
thrombocytopenia. Hepatopathy usually completely reverses after termination of
pregnancy. Patients are at increased risk for complications in future pregnancies
(Hay 2008, Westbrook 2010).
Undetermined
Despite dramatic improvements in diagnostic tests in approximately twenty percent
of patients with ALF, the etiology remains undetermined (Canbay 2009, Hadem
2008).
Molecular mechanisms and clinical presentation
As mentioned above, ALF occurs on the basis of acute hepatocellular injury caused
by toxic, viral or metabolic stress or hypotension. However, regardless of the initial
type of liver injury, ALF propels a series of events inducing hepatocellular necrosis
and apoptosis and reducing the regeneration capacity of the liver. Massive loss of
hepatocytes reduces the functional capacity of the liver for glucose, lipid and protein
metabolism, biotransformation, synthesis of coagulation factors, leading to
encephalopathy, coagulopathy, hypoglycemia, infections, renal and multi-organ
failure. In fact, even the pattern of hepatic cell death might  be of clinical
importance, as necrosis or apoptosis seem to be specific for different causes and are
associated with clinical outcome (Bechmann 2008, Volkmann 2008).
Apoptosis, programmed cell death, is a process in which ATP-dependant
processes lead to activation of caspases that induce a cascade of events, which ends
in the breakdown of the nucleus into chromatin bodies, interruption of membrane
integrity and finally total breakdown of the cell into small vesicles, called apoptotic
bodies. Upon massive cell injury, ATP depletion leads to necrosis with typical
swelling of the cytoplasm, disruption of the cell membrane, imbalance of electrolyte
homeostasis and karyolysis. Necrosis typically leads to local inflammation,
induction of cytokine expression and migration of inflammatory cells. However,
apoptosis itself might induce mechanisms that lead to necrosis and the ratio of
apoptosis vs. necrosis seems to play an important role in liver injury rather than the
individual events (Canbay 2004). This hypothesis is supported by observations that
a death receptor agonist triggers massive necrosis secondary to the induction of
apoptosis (Rodriguez 1996).
The rates of apoptosis or necrosis in ongoing ALF processes seem to be different
according to the underlying etiologies (Bechmann 2010). The degree of apoptosis
and necrosis, assessed by specific ELISA assays were significantly increased in
amanita intoxication compared to other causes. Apoptosis is the predominant type
of cell death in HBV and amanita-related ALF, vs. necrosis in acetaminophen and
congestive heart failure. Furthermore, entecavir treatment of fulminant HBV
Acute Liver Failure  531
significantly reduces serum cell death markers and improves clinical outcome
(Jochum 2009).
The regenerative capacity of the liver depends on the patient’s gender, age, weight
and previous history of liver diseases. Important mediators of liver regeneration
include cytokines, growth factors and metabolic pathways for energy supply. In the
adult liver, most hepatocytes are in the G0-phase of the cell cycle and non-proliferating. Upon stimulation with the proinflammatory cytokines tumour necrosis
factor α (TNFα) and interleukin- (IL-) 6, growth factors like transforming-growth
factor α (TGFα), epidermal growth factor (EGF) and hepatocyte growth factor
(HGF) are able to induce hepatocyte proliferation. TNF and IL-6 also induce
downstream pathways related to NFκB and STAT3 signaling. Both transcription
factors are mandatory for coordination of the inflammatory response to liver injury
and hepatocyte proliferation (Dierssen 2008). Emerging data supports an important
role for hepatic progenitor and oval cells as well as vascular endothelial growth
factor (VEGF) mediated angiogenesis in liver regeneration (Ding 2010, Dolle
2010).
TNFα, IL-1 and IL-6 are also important mediators of hyperdynamic circulation by
alterations of nitric oxide synthesis in ALF (Larson 2010). Renal failure, hepatic
encephalopathy, and brain edema are the results of these pathophysiologic changes.
Hyperammonemia correlates with brain edema and survival (Clemmesen 1999).
Decreased hepatic urea synthesis, renal insufficiency, the catabolic state of the
musculoskeletal system and impaired blood-brain barrier leads to ammonia
accumulation and alterations in local perfusion, which induces brain edema in ALF.
Interestingly, brain edema is a presentation of ALF rather than cirrhosis, and the risk
of brain edema increases with the grade of hepatic encephalopathy. After acute and
massive hepatic cell death, the release of proinflammatory cytokines and
intracellular material result in low systemic blood pressure leading to impairment of
splanchnic circulation. Indeed, renal failure in ALF patients is common, up to 70%
(Larsen 2011). Reduced qualitative and quantitative functions of platelets and
inadequate synthesis of prothrombotic factors are the causes of coagulopathy.
Leukopenia and impaired synthesis of complement factors in ALF patients increases
the risk for infections, which might result in sepsis. Infections increase the duration
of ICU stays and the mortality rate in ALF dramatically. With the impairment of
hepatic gluconeogenesis, hypoglycemia is a frequent feature of patients with ALF
(Canbay 2011).