Introduction Non-alcoholic fatty liver disease NAFLD is a medical condition that may progress to end-stage liver disease with the consequent development of cirrhosis and liver failure..
Trang 1from clinical trials evaluating promising medications
are discussed, as well as possibilities for the future
Introduction
Non-alcoholic fatty liver disease (NAFLD) is a medical
condition that may progress to end-stage liver disease
with the consequent development of cirrhosis and liver
failure The spectrum of NAFLD is wide, ranging from
simple fat accumulation in hepatocytes (steatosis)
with-out biochemical or histological evidence of inflammation
or fibrosis, through fat accumulation plus
necroinflam-matory activity with or without fibrosis (steatohepatitis
or NASH), to the development of advanced liver fibrosis
or cirrhosis (cirrhotic stage) All these stages are
his-tologically indistinguishable from those produced by
excessive alcohol consumption, but occur in patients
who deny alcohol abuse NASH is a histological
diag-nosis and represents only a stage within the spectrum
of NAFLD NAFLD should be differentiated from
steatosis with or without hepatitis resulting from
well-known secondary causes of fatty liver as they have
distinctly different pathogeneses and outcomes; these
disorders are listed in Chapter 1 (Table 1.2) and
dis-cussed in Chapter 21 The terms ‘NAFLD’ and ‘NASH’
are currently reserved for those patients in whom none
of the known single causes of fatty liver disease are
responsible for the liver condition Other liver diseases
that may present with a component of steatosis such as
viral or autoimmune hepatitis and metabolic/hereditary
liver diseases should be appropriately excluded These
other liver diseases may themselves be associated with
steatosis, and individuals suffering from these other
liver diseases may also have risk factors for NAFLD
(see Chapter 23) [1]
Obesity, type 2 (non-insulin dependent) diabetes
mellitus and hypertriglyceridaemia, common features
of the insulin resistance (metabolic) syndrome (IRS) (see
Chapter 5), are the most common risk factors or
co-existent conditions associated with NAFLD/NASH
Given the common occurrence and increasing
preva-lence of these comorbidities in the general population
(see Chapter 3), NAFLD seems to be the most
preva-lent liver disease in the USA and many other countries
Although the pathogenesis of NAFLD remains
un-known, insulin resistance represents the most
repro-ducible predisposing factor for this liver condition (see
Chapters 4 and 5) [2]
The natural history of NAFLD at its different stagesremains incompletely studied (see Chapters 3 and 14),but it is clear that some patients, particularly thosewith simple steatosis, follow a relatively benign course.Simple steatosis usually remains stable for many years,and will probably never progress in most patients [3].Thus patients who develop problems from NAFLDusually have NASH with advanced fibrosis, at least as
we currently understand this condition (see Chapters 1,
2 and 14) Hence, the decision to intervene with cal therapy should be aimed at arresting disease pro-gression and, ideally, be restricted to those patients
medi-at risk of developing advanced liver disease (NASHpatients and those with more advanced fibrosis)
In this chapter, we review existing medical therapyfor patients with NASH, the emerging data from clin-ical trials evaluating potentially useful medications, andthe potential therapeutic implications of recent studies
on the pathogenesis of this liver disease
Treatment of associated conditions
A large body of clinical and epidemiological data gathered during the last three decades indicates thatobesity, type 2 diabetes mellitus and hyperlipidaemiaare major associated conditions or predisposing factorsleading to the development of NAFLD Hence, it is reasonable to believe that the prevention or appropriatemanagement of these conditions would lead to improve-ment or arrest of the liver disease
NAFLD associated with obesity
Effects of weight loss
Weight loss improves insulin sensitivity (see Chapter 4),and NAFLD may resolve with weight reduction (seeChapter 15), but there are no randomized clinical trials
of weight control as treatment for this liver condition
An early report describes two patients whose biopsyshowed steatosis, necroinflammation and fibrosiswhich significantly improved following 11 and 20 kgweight loss, respectively over 1 year [4] In anotherreport, five obese patients stopped eating for some timeand lost 14–30 kg within 1 month Serum levels of liverenzymes appeared to be unaffected by starvation Thehepatic fat content decreased in three of them, butfibrosis became more prominent in four of the fivepatients [5] In another series [6], 10 obese patients
Trang 2who were treated with prolonged fasting for a mean of
71 days lost a mean of 41 kg and had a marked
reduc-tion in fatty infiltrareduc-tion However, areas of focal
necro-sis were more numerous and some patients developed
bile stasis Similar effects were noted in seven obese
sub-jects who experienced a mean weight reduction of 60
kg during a mean period of 5 months after treatment
with a diet of 500 kcal/day In this same series, 14
patients maintained a mean weight loss of
approxi-mately 65 kg for 1.5 years, and in nine of them the liver
biopsy findings normalized; there were only rare areas
of focal necrosis in the remaining five patients [6]
Another case series of 39 obese patients reported
marked biochemical improvement, particularly in
those patients who lost more than 10% of body weight
[7] Liver biopsies were not performed in any of these
patients In another series [8], 41 morbidly obese
patients with different stages of NAFLD had a median
weight loss of 34 kg during treatment with a very low
energy diet (388 kcal/day) The degree of fat
infiltra-tion improved significantly However, one-fifth of
patients, particularly those patients with more
pro-nounced reduction of fatty changes and faster weight
loss, developed slight portal inflammation or fibrosis
None of the patients losing less than 230 g /day or
approximately 1.6 kg /week developed fibrosis A
sig-nificant improvement in liver test results was noted
regardless of the histological changes
In a more recent study [9], liver biochemistries and
the degree of fatty infiltration improved significantly
in 15 obese patients with different stages of NAFLD
who were treated with a restricted diet (25 cal/kg /day)
plus exercise for 3 months Improvement in the degree of
inflammation and fibrosis also occurred in some patients
Weight reduction in obese children
Information regarding the effect of weight loss in
obese children with NAFLD is sparse (see Chapter 19)
In one case series [10], seven of nine obese children
with NAFLD who adhered to treatment with energy
restricting diet and increased exercise lost
approxim-ately 500 g /week This led to improvement in serum
aminotransferase (AT) levels and degree of hepatic
steatosis evaluated by ultrasonography Post-treatment
liver histology normalized in the only child who
under-went liver biopsy
In a more recent series [11], 33 obese children with
abnormal liver tests resulting from NAFLD underwent
6 months of treatment with a moderately energy
restrictive diet (mean 35 cal /kg /day; carbohydrates65%, protein 12%, fat 23%) plus aerobic exercise (≥ 6 h/week) to achieve a weight loss of approximately
500 g /week Liver tests became normal in all childrenwho lost weight, whereas the degree of steatosis evalu-ated by ultrasonography improved significantly or normalized in all children who lost ≤ 10% of bodyweight In another report [12], six obese children withNAFLD had improvement in serum AT with weightloss after a mean follow-up of 18 months
Optimal rate and extent of weight loss
Based on the analysis of these studies [4 –12], it is clearthat weight loss, particularly if gradual, may lead toimprovement in liver histology However, the rate anddegree of weight loss required for normalization ofliver histology have not been established It seems thatthe means by which or how fast weight loss is achieved
is important, and may have a critical role in mining whether improvement or more severe liverdamage results In patients with very extensive fattyinfiltration, pronounced reduction of fatty change and fast weight loss may promote portal inflammationand fibrosis Similarly, starvation or total fasting maylead to development of pericellular and portal fibrosis,bile stasis and focal necrosis [5,8] This paradoxicaleffect seen in some patients may be caused by increased circulating free fatty acid levels derived from fat mobilization and thus a greater rate of exposure of the liver to an unusually high concentration of freefatty acids Increased intrahepatic levels of fatty acidsfavour oxidative stress, lipid peroxidation and cytokineinduction, leading to a worsening of liver damage (seeChapters 7–10) Furthermore, serum AT levels almostalways improve or normalize with weight loss, but theyare poor predictors of worsening of liver histologydespite of or resulting from weight loss
deter-The National Heart, Lung and Blood Institute(NHLBI) and National Institute of Diabetes andDigestive and Kidney Diseases (NIDDK) expert panelclinical guidelines for weight loss recommend that theinitial target for weight loss should be 10% of baselineweight within a period of 6 months [13] This can beachieved by losing approximately 0.45 – 0.90 kg /week(1–2 lb/week) Following initial success, further weightloss can be attempted, if indicated, through furtherassessment The panel recommends weight loss usingmultiple interventions and strategies, including dietmodifications, physical activity, behavioural therapy,
Trang 3pharmacotherapy and surgery, or a combination of
these treatment modalities The recommendation for a
particular treatment modality or combination should
be individualized, taking into consideration the body
mass index and presence of concomitant risk factors
and other diseases The panel does not make specific
recommendations for the subgroup of patients with
NAFLD However, given the lack of clinical trials
in this area, the overall panel recommendations may
be a useful and safe first step for obese patients with
NAFLD Similarly, no specific recommendations were
made for monitoring of liver tests during weight loss
However, measuring serum AT once a month during
weight loss seems appropriate
Composition of dietary prescriptions
Different dietary energy restrictions have been used
However, further studies are necessary to determine
the most appropriate content of the formula to be
recommended for obese and/or diabetic patients with
NAFLD/ NASH In the absence of well-controlled
clin-ical trials in patients with NAFLD, it may be tempting
to recommend a heart-healthy diet as recommended
by the American Heart Association (AHA) for those
without diabetes [14], and a diabetic diet as
recom-mended by the American Diabetes Association (ADA)
for those with diabetes [15] Dietary
supplementa-tion with n-3 polyunsaturated and monounsaturated
fatty acids may improve insulin sensitivity and prevent
liver damage [16] Saturated fatty acids worsen insulin
resistance whereas dietary fibre can improve it
Never-theless, the effect of such dietary modifications on
the underlying liver disease in patients with NAFLD
remains to be established Diet to produce weight loss
should always be prescribed on an individual basis and
taking into consideration the patient’s overall health
Patients who have other obesity-related diseases such
as diabetes mellitus, hyperlipidaemia, hypertension or
cardiovascular disease will require close medical
super-vision during weight loss to adjust the medication
dosage as needed
Medications to reduce weight
Medications used to reduce body weight currently
approved by the Food and Drug Administration include
orlistat, phentermine and sibutramine Their use results
in weight reduction in many patients, but their effects
on the liver disease remain undefined Two small case
series [17,18] suggest that weight loss achieved
dur-ing treatment with the gastrointestinal lipase inhibitororlistat may improve liver disease in obese patients.However, orlistat has been associated with cases ofhepatotoxicity [19], and it therefore remains to beproven whether the risk : benefit ratio of orlistat orother weight-reducing medications justifies their usefor the treatment of NAFLD
Surgical approaches to weight reduction
Malabsorptive procedures (jejuno-ileal bypass, pancreatic diversions), popular weight-reducing surgicalprocedures in the 1960s and 1970s, have been virtuallyabandoned, mainly because of the high frequency ofsevere postoperative complications including worsening
bilio-of liver disease (see Chapter 20) [20] The developmentand worsening of NAFLD in obese patients undergoingbariatric surgery may be caused by a combination ofadditive factors including protein or calorie malnutri-tion, increased fluxes and liver exposure to free fattyacids, and bacterial overgrowth in the defunctionalizedintestinal segment In this regard, enteral and parenteralsupplementation of amino acids and proteins may be ofbenefit [21] In a series of 33 obese patients undergoingintestinal bypass [22], metronidazole given at randomintervals after surgery led to a significant improvement
or normalization in the degree of steatosis
Restrictive procedures to achieve weight loss (gastricbypass, gastroplasty) are safer than malabsorptive pro-cedures In 1999, the US Food and Drug Administrationapproved adjustable gastric banding as a weight-reducing procedure The adjustable gastric band seems
to be safer for liver disease because of the more gradualweight loss achieved (approximately 2.7–4.5 kg/month[6–10 lb/month]) [23]
Parenteral nutrition
Patients receiving long-term total parenteral tion may develop fatty liver (see Chapter 21), partiallybecause of choline deficiency Choline supplementationhas been reported to improve or revert hepatic steatosis[24,25] Similarly, bacterial overgrowth in the restingintestine along with the lack of enteral stimulation hasbeen implicated in the genesis of liver damage, includ-ing NAFLD, in patients on long-term total parenteralnutrition Polymyxin B, a non-absorbable antibioticthat specifically binds to the lipid A-core region of lipopolysacharide [26] and metronidazole [27] hasbeen shown to significantly improve the degree of fatty infiltration and reduce the production of tumour
Trang 4nutri-necrosis factor (TNF), a key molecule in the
devel-opment of insulin resistance in rats receiving total
parenteral nutrition
NAFLD/NASH associated with diabetes mellitus and
hyperlipidaemia
Obese patients with diabetes mellitus and /or
hyper-lipidaemia should be enrolled in a weight control
pro-gramme The NHLBI / National Institutes of Health
(NIH) [13], AHA [14] and ADA [15] expert panel
recommendations may be useful for these patients (see
above) However, the effect of such recommendations
on liver disease in diabetic or hyperlipidaemic patients
have not been studied systematically Furthermore,
the appropriate control of glucose and lipid levels in
patients with diabetes and hyperlipidaemia is not always
effective in reversing NAFLD
In obese ob/ob mice, an animal model of steatosis
that develops insulin resistance, diabetes and
hyper-lipidaemia [28], metformin, an oral antidiabetic
med-ication, led to improvement in liver tests and degree
of steatosis Based on these findings, metformin and
other insulin-sensitizing medications are being
evalu-ated in humans with NAFLD (see later section and
Chapter 24) Patients with type 1 (insulin-dependent)
diabetes mellitus and hepatomegaly show
improve-ment in symptoms of hepatomegaly when appropriate
control of hyperglycaemia is achieved
Hypertriglyc-eridaemia, rather than hypercholesterolaemia, is a risk
factor for NAFLD (see Chapters 1 and 3) In this
regard, gemfibrozil, atorvastatin and probucol but not
clofibrate may improve the liver condition (see p 201
and Chapter 24)
NAFLD ‘without’ risk factors
A subgroup of patients with liver biopsy-proven NAFLD/
NASH have normal body mass index and normal waist
: hip ratio as well as normal glucose tolerance and
normal lipid profile These NAFLD patients who lack
the most common associated risk factors are candidates
for other treatment modalities such as pharmacological
therapy Also, although further work is necessary,
this subset of patients with NAFLD may still be insulin
resistant, and so improving insulin sensitivity through
changing diet composition as opposed to caloric
restriction, as well as increasing physical activity, may
improve insulin sensitivity and lead to improvement
of the liver disease
Drugs and hepatotoxins
Several drugs and environmental exposure to somehepatotoxins have been recognized as potential causes offatty liver, steatosis, steatohepatitis and even cirrhosis(see Chapter 21) [29] The liver conditions resultingfrom these secondary causes differ to some extent fromNAFLD in pathogenesis, pathology and outcomes How-ever, a drug cause should always be sought in patientswith NAFLD because withdrawal of a causative agent,when possible, can often lead to resolution of the liverdisease
Pharmacological therapy
Because rapid weight loss may worsen NAFLD/NASH,and weight control is a difficult task to accomplish for most obese patients, use of medications that candirectly reduce the severity of liver damage independent
of weight loss is a logical alternative Pharmacologicaltherapy may also benefit those patients who lack themost common risk factors or associated conditions,although it is becoming highly questionable whether suchindividuals, in the absence of central obesity or insulinresistance, have significant NASH (see Chapters 3, 5and 15) The decision to intervene with pharmacologicaltherapy aimed at the underlying liver disease is based
on the anticipated risk of progression to severe liverdisease However, pharmacological therapy directedspecifically at the liver disease has only recently beenevaluated in patients with NAFLD Most of these studies have been uncontrolled, open-label and lasting
1 year or less, and only a few of them have evaluatedthe effect of treatment on liver histology Several studies are currently in progress, but some preliminaryresults have been reported (updated information ispresented in Chapter 24)
Insulin-sensitizing medications (Table 16.1)Type 2 diabetes mellitus and truncal (central) obesityare well-known conditions associated with resistance
to normal peripheral actions of insulin Indeed, insulinresistance represents the most reproducible predisposingfactor for NAFLD, being present in more than 95% ofcases, with more than 85% having other manifesta-tions of the insulin-resistance (metabolic) syndrome (see Chapter 5) Hence, it is reasonable to speculate thatthe use of medications that improve insulin sensitivity
Trang 5may benefit the liver disease of patients with associated
insulin-resistance conditions Thiazolidinediones, more
commonly termed glitazones (troglitazone, rosiglitazone,
pioglitazone), are a new class of antidiabetic drugs that
act as PPARγ agonists, thereby selectively enhancing
or partially mimicking certain actions of insulin The
resultant beneficial effects include an
antihypergly-caemic effect, frequently accompanied by a reduction
in circulating concentrations of insulin, triglycerides
and non-sterified (free) fatty acids
Troglitazone
Troglitazone (400 mg /day) was given to 10 patients
with liver biopsy-proven NASH for 3– 6 months [30]
Alanine aminotransferase (ALT) levels normalized in
seven patients and, although features of NASH remained
in the post-treatment liver biopsy, the grade of
necro-inflammation improved in four parients Troglitazone
proved to be hepatotoxic and was withdrawn from the
market after the report of several dozen deaths or cases
of severe hepatic failure requiring liver transplantation
[31] There is little evidence to indicate underlying
liver disease in those who experienced
troglitazone-induced liver failure [31]
Rosiglitazone
Rosiglitazone (4 mg twice daily) was given to 25 patients
with liver biopsy-proven NASH for 1 year [32,33] Liverenzymes including aspartate aminotransferase (AST),alkaline phosphatase and γ-glutamyl transpeptidase(GGT) improved significantly as well as the degree ofinsulin sensitivity as determined by quantitative insulin-sensitive check index (QUICKI) Post-treatment liverbiopsies were performed and showed a significantimprovement in the degree of centrilobular fibrosis[33] (and see Chapter 24) In this study, one patientexperienced an abrupt rise in AT levels possibly related
to rosiglitazone, and some cases of possible induced liver injury related to rosiglitazone have beenreported [31] Hence, not only the efficacy, but also thesafety of rosiglitazone in patients with NAFLD needs
drug-to be evaluated in larger placebo-controlled trials withextended follow-up
Pioglitazone
Pioglitazone has been evaluated in three pilot studies,and the preliminary results reported in abstracts [34 –36] (and see Chapter 24) In one study [34], pioglita-zone was given to eight patients with NASH for amean of 28 weeks (range 8 – 48 weeks); normaliza-tion of AT occurred in five patients, with decrease toapproximately 50% of the baseline value in two others.Steatosis improved in the only patient who had post-treatment liver biopsy performed
Table 16.1 Insulin-sensitizing medications evaluated in the treatment of non-alcoholic fatty liver disease.
Duration of
Study [Reference] Drug patients Type of study with (months) Aminotransferases Histology
Caldwell et al (2001) [30] Troglitazone 10 Open-label Baseline 3– 6 Improved Improved
Acosta et al (2001) [34] Pioglitazone 8 Open-label Baseline 2–12 Improved ND
Marchesini et al (2001) [37] Metformin 14 Open-label Baseline 4 Improved ND
Nair et al (2002) [38] Metformin 25 Open-label Baseline 6 Improved ND
Neuschwander-Tetri et al Rosiglitazone 25 Open-label Baseline 12 Improved Improved (2002) [32,33]†
Loguercio et al (2002) [59] Probiotics 10 Open-label Baseline 2 Improved ND
Sanyal et al (2002) [35] Pioglitazone 21 Randomized Baseline; 6 Improved* Improved*
+ vitamin E (open-label) vitamin E
Trang 6In another pilot study [35], 10 patients with
NASH were treated with pioglitazone (30 mg/day) plus
vitamin E (400 IU/day) and compared to 11 patients
treated with the same regimen of vitamin E alone After
6 months of therapy, ALT decreased in both groups as
well as the degree of steatosis, ballooning of
hepa-tocytes and Mallory hyaline However, the histological
improvement was more marked in the combination
group In this study [35], one patient in the
combina-tion group had a worsening of liver enzymes, possibly
related to pioglitazone, and had to be withdrawn
Some cases of possible drug-induced liver injury have
been reported with pioglitazone [31]
Pioglitazone (30 mg /day) was given to nine patients
with NASH for 1 year in an open-label pilot study
[36] Improvement or normalization of AT as well as
improvement in the degree of insulin resistance occurred
at the end of treatment Also, a significant improvement
in severity of steatosis, necroinflammation and Mallory
hyaline was noted on liver biopsies performed at the
end of treatment Pioglitazone was well tolerated, but
there was a significant gain in body weight and total
body fat The promising results of these three pilot
studies along with the long-term safety of pioglitazone
in patients with NASH need to be evaluated in
well-controlled clinical trials
Metformin
Metformin is an antidiabetic medication that improves
insulin sensitivity In ob/ob mice, an animal model of
fatty liver, metformin reversed hepatomegaly as well as
steatosis and AT abnormalities [28] These beneficial
effects of metformin seemed to be through inhibiting
hepatic expression of TNF and TNF-inducible factors
that promote hepatic lipid accumulation, such as steroid
regulatory element binding protein-1 (SREBP-1), and
factors promoting hepatic adenosine triphosphate (ATP)
depletion, such as uncoupling protein-2 (UCP-2) [28]
Based on these results, a regimen of metformin 500 mg
three times daily was given for 4 months to 14 patients
with NASH [37] Metformin therapy was associated
with a significant improvement in liver tests and glucose
disposal, an index of insulin sensitivity, as well as a
significant decrease in hepatic volume and body mass
index
In another pilot study [38], 25 patients were treated
with metformin (20 mg /kg /day) At 6 months of
therapy, patients had a significant decrease in body
weight and AT levels Unfortunately, the effect on
liver histology has not been evaluated in any study.Metformin was well tolerated in these studies, but itshould be noted that although no patient developedlactic acidosis, serum lactic acid levels did rise [37].Thus, larger controlled trials are needed to determinethe safety and efficacy of metformin in the treatment
of NAFLD
Antioxidants
In patients with NAFLD, antioxidant therapy may
be potentially useful in preventing progression fromsteatosis to steatohepatitis and fibrosis (see Chap-ters 7–10) Antioxidants that have been evaluated inpatients with NAFLD include vitamin E (α-tocopherol),
vitamin C, betaine, N-acetylcysteine and iron
deple-tion (Table 16.2) Vitamin E, a potent antioxidant that
is particularly effective against membrane lipid dation, suppresses expression of TNF, interleukin 1(IL-1), IL-6 and IL-8 by monocytes and/or Kupffercells, and inhibits liver collagen-α1(I) gene expression
peroxi-Vitamin E ( α-tocopherol)
A recent study reported the results of treatment with α-tocopherol in 11 children with a clinical diagnosis ofNAFLD [39] Vitamin E (400–1200 IU/day orally) wasgiven for 4–10 months and led to a significant improve-ment in liver tests In another study [40], α-tocopherol
in a regimen of 300 mg/day was given for 1 year to
12 patients with liver biopsy-proven NASH, and 10patients with a clinical diagnosis of NAFLD Liver testsimproved significantly compared to baseline, whereasthe degree of steatosis, inflammation and fibrosisimproved or remained unchanged in the nine patientswith NASH who had post-treatment liver biopsy per-formed Plasma levels of transforming growth factor-β1 (TGF-β1) in patients with NASH were reducedsignificantly with α-tocopherol treatment [40]
In another study [41], 45 patients with NASH wererandomized to treatment with the combination of vitamin E (1000 IU/day) plus vitamin C (1000 IU/day), or an identical placebo for 6 months At the end
of therapy, 48% of patients in the vitamin group and41% in the placebo group showed improvement in atleast one stage of fibrosis Although the score for stage
of fibrosis was statistically lower post-treatment pared to baseline in the vitamin group, changes post-treatment were not statistically different between thevitamin and placebo groups Also, liver enzymes andthe degree of steatosis and necroinflammatory activity
Trang 7com-were not significantly affected by treatment Thus,
6 months of therapy with the combination of vitamin
E plus vitamin C was not better than placebo at
improving the liver disease in patients with NASH
However, given the high proportion of patients in the
placebo group who appeared to improve fibrosis stage
at 6 months, the study [41] did not have enough power
to detect a benefit from treatment with these vitamins
It is concluded that larger controlled trials are still
warranted to better define the potential efficacy of
vitamin E for patients with NAFLD
Betaine
Betaine, a normal component of the metabolic cycle
of methionine, increases S-adenosylmethionine levels,
which in turn protects the liver from ethanol-induced
triglyceride deposition in rats In a recent study [42],
betaine 20 mg/day was given to eight patients with
NASH After 1 year of treatment, a significant
improve-ment or normalization of serum AT levels was noted,
whereas the degree of steatosis, necroinflammatory
activity and fibrosis improved or remained unchanged
in all patients Based on these results, a larger
placebo-controlled trial is now in progress
In another study [43], 191 patients with a clinical
diagnosis of NAFLD were randomized to treatment
with betaine glucuronate (300 mg/day) in combination
with diethanolamine glucuronate and nicotinamideascorbate (96 patients), or placebo (95 patients); theywere treated for 8 weeks A significant improvement
in right upper quadrant abdominal discomfort, liverenzymes, hepatomegaly and the degree of steatosisevaluated by ultrasonography was noted at the end oftreatment with combination therapy; such changes didnot occur in the placebo group Unfortunately, becauseliver biopsies were not performed and the treatmentperiod was too short, it is difficult to derive meaningfulconclusions from this study
N-acetylcysteine N-acetylcysteine is a glutathione prodrug that increases
glutathione levels in hepatocytes In turn, this countershepatocyte production of reactive oxygen species (ROS)and hence prevents the development of oxidative stress
in liver cells In a pilot study [44], 11 patients with
NASH were treated with N-acetylcysteine (1 g /day)
for 3 months A significant improvement in AT levelsoccurred at the end of treatment, but unfortunatelyliver histology was not evaluated
Phlebotomy
Although the role of iron in the pathogenesis anddevelopment of more severe liver injury in patientswith NAFLD remains controversial (see Chapters 1, 2,
Table 16.2 Antioxidant medications evaluated in the treatment of non-alcoholic fatty liver disease.
Abdelmalek et al (2001) [42] Betaine 8 Open-label Baseline 12 Improved Improved
Gulbahar et al (2000) [44] N-acetylcysteine 11 Open-label Baseline 3 Improved ND Lavine (2000) [39]† Vitamin E 11 Open-label Baseline 4–10 Improved ND
Hasegawa et al (2001) [40] Vitamin E 22 Open-label Baseline; 12 Improved Improved‡
† Study performed in children.
‡ Liver biopsy performed in nine patients post-treatment.
§ Improvement in degree of fibrosis.
Trang 85 and 7), iron has been hypothesized to induce
oxida-tive stress by catalysing production of ROS Two pilot
studies involving a total of 30 patients with NASH have
been reported [45,46] Quantitative phlebotomy was
performed to induce iron depletion to a level of
near-iron deficiency The two studies reported a significant
improvement in AT levels
In another recent study [47], 17
carbohydrate-intolerant patients with the clinical diagnosis of
NAFLD were treated with quantitative phlebotomy to
induce iron depletion to a level of near-iron deficiency
Serum ALT levels improved to near normal and there
was also improvement in insulin sensitivity,
unfortun-ately, liver biopsy was not performed in any of these
studies, and thus, the effect of iron depletion on liver
histology in patients with NAFLD remains uncertain
Lipid-lowering medications
Clofibrate
Clofibrate is a lipid-lowering drug that decreases
the hepatic triglyceride content in rats with
ethanol-induced hepatic steatosis [48] Based on this, a pilot
study was performed to evaluate the usefulness of
clofibrate (2 g /day) in the treatment of patients with
NASH [49] After 1 year of treatment, no significant
changes in liver tests or histological features were noted
Gemfibrozil
In a recent report [50], 46 patients with NASH were
randomized to treatment with gemfibrozil 600 mg/day
for 4 weeks or no treatment A significant improvement
in AT levels was noted with gemfibrozil compared to
baseline values, and this did not occur in the untreated
patients Body weight remained unchanged during
treatment, and improvement in liver tests seemed to be
independent of baseline triglyceride levels
Atorvastatin
In another pilot study [51], seven patients with NASH
and hyperlipidaemia were treated with atorvastatin
(10 –30 mg /day) for up to 12 months At the end of
therapy, there was a significant improvement in serum
lipid levels as well as the degree of hepatic
inflamma-tion, ballooning and Mallory hyaline on liver biopsy
These positive results need to be reproduced in a
placebo-controlled trial
Probucol
Probucol is another lipid-lowering medication that
has insulin-sensitizing properties Thirty patients with
NASH were randomized to therapy with probucol(500 mg/day) or an identical placebo and treated for
6 months [52] Improvement or normalization of ATlevels was significantly greater or more common in the probucol than the placebo group and this was independent of changes in body weight or serum lipidlevels Post-treatment liver biopsy was not performed
It is therefore uncertain whether probucol improvesliver histology Probucol may cause severe, sometimesfatal cardiac arrhythmias and was withdrawn from themarket in the USA in 1995; as a consequence, there islittle enthusiasm in evaluating probucol in a larger trial
Ursodeoxycholic acidUrsodeoxycholic acid (UDCA) is the non-hepatotoxicepimer of chenodeoxycholic acid During UDCA treat-ment, UCDA replaces endogenous bile acids, which are dose-dependent hepatotoxins UDCA has mem-brane stabilizing or cytoprotective effects exerted
on mitochondria, as well as immunological effects.Hydrophobic bile acids increase cellular damage andoxidative stress in steatotic hepatocytes By decreasinghydrophobic bile acids, UDCA could protect againsthepatocyte injury and decrease oxidative stress inpatients with NAFLD Also, treatment with UDCA leads
to less production of TNF, which, in turn, may improveinsulin sensitivity UDCA has been used in the treat-ment of some hepatobiliary diseases for approximatelytwo decades Thus, unlike other medications evaluatedfor patients with NAFLD, there are abundant data onthe safety of long-term use of UDCA in patients withliver disease
Four open-label pilot studies have evaluated thetherapeutic benefits of UDCA in adults with NASH Inone of these studies [49], 24 patients received UDCA
in a regimen of 13–15 mg /kg /day for 12 months Thisled to a significant improvement in liver tests and thedegree of hepatic steatosis compared to baseline Inanother study [53], liver tests normalized or signific-antly improved after 6 months of treatment with UDCA(10 mg /kg /day) in 13 patients with NASH Similarly,among 31 patients with NASH randomized to UDCA(10 mg /kg /day) plus low-fat diet or low-fat diet alonefor 6 months, normalization of liver tests was signific-antly more common among those treated with UDCAplus diet than with diet alone [54] In the most recentstudy [55], UDCA (250 mg three times daily) given for6–12 months improved AT levels in 24 patients with
Trang 9NASH; UDCA therapy also improved several serum
markers of fibrogenesis
Based on these results, we developed a large-scale
multicentric placebo-controlled trial of UDCA in patients
with NASH A total of 168 patients were enrolled and
randomized to UDCA (13–15 g /kg /day) or identical
placebo and treated for 2 years The study has recently
been completed and the results will soon be analysed
and reported (see Chapter 24)
Future directions
In order to develop effective medical therapy for
patients with NAFLD, further work is clearly needed
to enhance our understanding of the pathogenesis and
natural history of this condition (see Chapters 3, 7–12
and 14) Some lines of evidence, albeit still
inconclus-ive, indicate that oxidative stress/lipid peroxidation,
bacterial toxins, overproduction of TNF, alteration of
hepatocyte ATP stores and CYP2E1 and 4A enzyme
activity may have a role in the genesis and progression
of NAFLD
Regardless of the cause, acute or chronic hepatic
steatosis is associated with lipid peroxidation; this
seems to increase with the severity of steatosis [56]
and with NASH versus steatosis (see Chapter 12); the
end-products of lipid peroxidation stimulate collagen
production and fibrogenesis Further studies should
focus on increasing antioxidant defences through dietary
and/or pharmacological manipulations
Because metronidazole and polymyxin B may
pre-vent the development of NAFLD in obese patients
undergoing intestinal bypass, as well as in rats
receiv-ing total parenteral nutrition [22,26,27], a role of
endotoxin- and/or cytokine-mediated injury has been
suggested as a contributing factor for the
develop-ment of NAFLD (see Chapter 10) Furthermore, it has
been shown that genetically obese mice are very
sensi-tive to the effect of lipopolysacharide in developing
inflammation in the setting of steatosis [57]
More recently, treatment with probiotics or anti-TNF
antibodies improved liver steatosis and
inflamma-tion and decreased ALT levels in obese leptin-deficient
ob/ob mice [58] The treated animals had decreased
hepatic expression of TNF messenger RNA, reduced
activity of Jun N-terminal kinase (a TNF-regulated
kinase that promotes insulin resistance) and decreased
DNA binding activity of nuclear factor κB (NF-κB),
the target of inhibitor of κB kinase β (IKK-β), anotherenzyme that causes insulin resistance (Chapters 5 and 10) In a recent case series [59], 10 patients withNASH who were treated for 2 months with a mixture
of different bacteria strains showed a significantimprovement in liver enzymes, serum levels of TNFand end-products of lipid peroxidation when com-pared to baseline, but post-treatment liver biopsieswere not performed Hence, if this concept is valid, thepotential benefit of intestinal decontamination or modi-fication of the intestine microflora with probiotics, theadministration of soluble cytokine receptors and neu-tralizing anticytokine antibodies as well as biopharma-ceuticals with anti-TNF activity may warrant furtherevaluation as therapies for patients with NAFLD.Hepatocyte ATP stores in patients with NASH seemvulnerable to depletion compared to lean controls [60].Hence, treatment efforts primarily directed toward pro-tecting hepatocyte ATP stores might potentially benefitpatients with NAFLD Similarly, CYP2E1 and 4Aactivity may contribute to hepatotoxicity in mice andhumans with NAFLD [61– 63] Treatment strategies
to limit its activity, such as dietary modifications reduced diet), may be beneficial
(fat-Patients with NAFLD may develop advanced liverfibrosis and progress to end-stage liver disease Fibrosisrepresents the most worrisome feature on liver biopsy
in patients with NAFLD, indicating a more severe and potentially progressive form of liver injury Thedevelopment of antifibrotic therapies aimed at the under-lying liver disease is an attractive yet unaccomplishedgoal However, substantial advances on our under-standing of the molecular mechanisms of liver fibrosismade in the last decade have led to the development ofnew agents that inhibit stellate cell and/or myofibro-blast proliferation and collagen synthesis [64,65] Many
of these agents have proved antifibrogenic in in vitro
studies, but only a few agents are tolerable or effective
in suitable animal models in vivo Agents with
anti-fibrotic effects that may hold promise for patients withNAFLD/ NASH are silymarin (a mixture of flavonoidsthat also have antioxidant properties), pentoxifylline(a phosphodiesterase inhibitor) and pentifylline (a morepotent pentoxifylline derivative), LU135252 (an oralinhibitor of the endothelin A-receptor), angiotensin Ireceptor antagonists or angiotensin-converting enzymesinhibitors, and profibrogenic cytokines antagonists(soluble TGF-β1 receptor antagonists or adenoviralTGF-β1 blocking constructs)
Trang 10The encouraging results of pilot studies with
insulin-sensitizing drugs, antioxidants, lipid-lowering and
hepa-toprotective medications (Tables 16.1–16.4) warrant
their further evaluation in clinical trials However,
in order to make solid recommendations of routine
administration of any of the previously evaluated (or
other) medications in the treatment of patients with
NAFLD/NASH, further well-controlled clinical trials
are clearly necessary These studies must have enough
power, adequate duration of follow-up, and should
also include clinically relevant end-points In
particu-lar, simple improvement or normalization of liver tests
and/or the degree of steatosis on imaging studies, as
used in most of the pilot studies reported to date, do
not necessarily imply that these agents will have a real
effect on the natural history (fibrotic progression) of this
liver disease Similarly, although improvement of liver
histology may possibly be a more accurate surrogate
marker of a better long-term prognosis, a beneficialmedication for patients with NAFLD should be notonly safe and well tolerated, but also prove beneficial inimproving health-related quality of life [66,67] It shouldalso be cost-effective, bearing in mind the other morbid-ity of at-risk patients (obesity, type 2 diabetes, hyper-lipidaemia, arterial hypertension), and the unknowncost-efficacy of lifestyle interventions
Although an ideal end-point in clinical trials would
be a delay in developing liver-related complications andimprovement of long-term survival, such end-pointsmay not be practical given the slowly progressive nature
of this condition Because NAFLD progresses slowlyover many years, hundreds of patients with this condi-tion would need to be enrolled in prospective clinicaltrials and followed-up for a number of years, perhapsdecades, in order to see a real effect of a medication
on long-term survival It may be unrealistic to believe
Table 16.3 Lipid-lowering medications evaluated in the treatment of non-alcoholic fatty liver disease.
Duration of
Study [Reference] Drug patients Type of study with (months) Aminotransferases Histology
Laurin et al (1996) [49] Clofibrate 16 Open-label Baseline 12 No improvement No
improvement
Basaranoglu et al (1999) Gemfibrozil 46 Randomized No treatment 1 Improved ND
Horlander et al (2001) [51] Atorvastatin 7 Open-label Baseline Up to 12 No improvement Improved*
Merat et al (2003) [52] Probucol 30 Randomized Placebo 6 Improvement ND
(double blind)
ND, not done
* Improvement in the inflammation, ballooning, Mallory hyaline and total histological score.
Table 16.4 Ursodeoxycholic acid for the treatment of non-alcoholic fatty liver disease.
Duration of
Study [Reference] Drug patients Type of study with (months) Aminotransferases Histology
Laurin et al (1996) [49] UDCA 24 Open-label Baseline 12 Improved Improved
Guma et al (1997) [53] UDCA + diet 24 Randomized Baseline 6 Improved† ND
(open-label) Diet alone
Ceriani et al (1998) [54]† UDCA + diet 31 Open-label Baseline 6 Improved† ND
Diet alone
Holoman et al (2000) [55] UDCA 24 Open-label Baseline 6 –12 Improved ND
ND, not done
UDCA, ursodeoxycholic acid.
† Greater biochemical improvement with UDCA + diet.
Trang 11that such a study is both feasible for the patients
and affordable Better identification of those patients
with NAFLD/ NASH who are at risk of progressing to
end-stage liver disease may allow selective enrolment
in therapeutic trials of those ‘high-risk’ patients who,
in theory, would be expected to derive the most benefit
from medical therapy Although this still has to be
proven in population-based studies, those patients with
NAFLD at high risk for disease progression seem to be
those with necroinflammatory activity (NASH) on liver
biopsy as well as those patients with more advanced
fibrosis (see Chapters 3 and 14) Thus, until further
work is carried out, we believe that further clinical
trials should focus on patients with liver
biopsy-proven NASH and those with more advanced fibrosis
Conclusions
Management of associated conditions or risk factors
for NAFLD, including obesity, diabetes mellitus and
hyperlipidaemia, may improve the liver disease Gradual
weight loss should be sought, particularly with the
combination of diet and increased physical activity
Total starvation or very low-energy diets may cause
worsening of liver histology, and should be avoided
Improvement in liver test results, particularly AT, is
almost universal in obese children and adults after
weight reduction, but liver test results are poor
indica-tors of worsening of liver histology after weight loss
Emerging data from small pilot studies suggest that
several insulin-sensitizing, antioxidant, lipid-lowering
and hepatoprotective medications may be of benefit
However, such agents must now to be evaluated in
well-controlled clinical trials with extended follow-up and
clinically relevant end-points, particularly fibrosis
pro-gression Improved understanding of the pathogenesis
and natural history of NAFLD, along with recent
advances in the understanding of molecular
mecha-nisms involved in liver fibrosis, should lead to
develop-ment of new medical therapies targeted to patients at
‘high risk’ for disease progression
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Trang 14Non-alcoholic fatty liver disease (NAFLD) and
non-alcoholic steatohepatitis (NASH)aa severe form of
NAFLDahas produced an ironic combination of adverse
effects for orthotopic liver transplantation (OLT), in
that NAFLD has increased the need for donor livers
at the same time as decreasing the number of donors
available Increasing evidence indicates that NASH
cirrhosis and NASH-related cryptogenic cirrhosis can
progress to end-stage liver disease, now accounting for
as many as 10% of patients undergoing OLT
Unfortunately, the high prevalence of NAFLD
(asso-ciated with the epidemic of obesity and diabetes) in
the population has decreased the donor pool Because
livers with steatosis (macrovesicular more so than
microvesicular) result in poor post-OLTx outcomes,
including primary graft non-function and decreased
patient and graft survival, livers containing more than
30 –50% of fat are usually not accepted as donors The mechanism that these fatty livers perform poorly
is related to a combination of diminished blood flow,poor membrane function, impaired energy productionand oxidative stress These issues affect both cadaverand living donor livers
Hepatic steatosis is also common and affects otherforms of end-stage liver disease, in particular patientswith hepatitis C virus (HCV) infection Fatty liver andrelated fibrosis may occur post-transplant in patientswho had NASH or cryptogenic cirrhosis prior to the
liver transplant or it can occur de novo and adversely
affect outcomes It is now clear that hepatic steatosisand its comorbidities associated with the insulin resist-ance syndrome (obesity, diabetes, hypertension anddyslipidaemias) impact the clinical outcomes and man-agement issues of these patients Therefore it is import-ant for transplant physicians to be aware of the clinicalrelevance of fatty liver and its relationship with the
NAFLD, NASH and orthotopic liver transplantation
Anne Burke & Michael R Lucey
17
Key learning points
1 NASH cirrhosis and NASH associated cryptogenic cirrhosis now account for 5–10% of the liver
trans-plantation performed in the United States
2 The degree of steatosis (macrovesicular more so than microvesicular) of the donor liver is directly related
to primary non-function and graft survival post-transplant Potential donor livers containing more than
30 –50% fat are usually not accepted
3 NASH and cryptogenic cirrhosis frequently recur or develop de novo post-transplant independently from
the immunosuppressive drugs used post-transplant
4 Transplant physicians need to recognize the clinical importance of hepatic steatosis and the metabolic
syndrome both before and after liver transplantion
Edited by Geoffrey C Farrell, Jacob George, Pauline de la M Hall, Arthur J McCullough
Copyright © 2005 Blackwell Publishing Ltd
Trang 15insulin resistance syndrome and its comorbidities while
performing patient selection and formulating targeted
therapeutic strategies in these patients
Introduction
NAFLD and NASH are becoming increasingly common
in the population We discuss here the impact of these
conditions on OLT In particular, we review the
litera-ture regarding the use of steatotic donor livers; NAFLD
as a cause of end-stage liver disease requiring liver
transplantation and the evaluation of NAFLD patients
for OLT; recurrence or de novo NAFLD post-OLT; and
the management of NAFLD both pre- and post-OLT
Use of steatotic livers for liver
transplantation
The demand for OLT continues to outstrip the supply
of available cadaveric donor livers and each year
many patients with end-stage liver disease die for lack
of a suitable donor liver Every year more than 1000
patients on the waiting list die without a liver
trans-plant [1] Steatosis of the donor liver is associated
with an increased risk of primary non-function in the
allograft, which may result in mortality or
require-ment for retransplantation [2] Thus, a tension exists
between the wish to put every potential donor liver to
use and the wish to avoid primary non-function
Primary non-function
Primary non-function (PNF) is defined as allograft
fail-ure within 7 days of OLT in the absence of technical
problems such as hepatic artery thrombosis, biliary
obstruction or dehiscence of the bile duct anastamosis
PNF is accompanied by increasing coagulopathy, rising
bilirubin and the excretion of thin pale bile The latter
observation can be made in those recipients with a
biliary drainage cannula PNF has a high mortality and
usually requires relisting and emergent
retransplanta-tion Outcomes for retransplantation are less favourable
than for primary transplantation (69% versus 87%
1-year survival) [1]
Poor early graft function is a variant of PNF in
which hepatic function fails to advance as expected,
albeit with more modest derangement of coagulation
and biliary excretion Poor early graft function mayresolve with careful medical management, but it increasesthe cost by extending ICU stay and sometimes neces-sitates retransplantation
Prevalence of NAFLD/NASH in donorsSteatosis is typically non-uniform and is difficult toassess accurately, particularly when it is less severe
In a review of more than 500 consecutive medicolegalautopsies following road traffic accidents, 24% ofcadavers were found to have a fatty liver [3,4] Accord-ing to the estimates of 94 liver transplant surgeons fromthe UK and USA, the degree of steatosis ranged from20% to 40% in approximately half of all retrieved livers, and a further 14 –19% donor livers showed
40 – 60% steatosis [5] The diagnosis of steatosis of thedonor liver was often based on clinical impression Forexample, in the survey cited above, 12 of 94 surgeonsdeclared that they undertook a liver biopsy in everypotential donor, but eight of 94 said that they nevertook a biopsy to determine fat content in any donor.There remained 70 of 94 who said that they took one or more biopsies whenever they were concernedabout the appearance of the liver or the donor had risk factors for steatosis
Outcomes after transplantation using steatoticdonor livers
There is evidence to support the belief that vesicular steatosis is associated with increased rates ofPNF and poorer outcome For example, the outcomes
of 59 patients receiving livers with up to 30% vesicular steatosis were worse than those observed in
macro-57 patients receiving livers without fatty infiltration.The recipients of the steatotic livers had higher rates
of PNF (5.1% compared to 1.8%) and worse 2-yearpatient survival (77% compared to 91%) and graftsurvival (70% compared to 82%) [6] A retrospectivestudy of 443 patients showed that increasing donorsteatosis grade was associated with 1-month but not 3- or 12-month allograft loss [7] In both of these stud-ies, recipient status was similarly distributed betweenthe varying grades of steatosis, refuting the concernthat poorer outcomes among recipients of fatty liversare confounded by greater severity of illness pre-OLT
In contrast, microvesicular steatosis does not seem
to carry the same risk of PNF as does macrovesicular
Trang 16steatosis In a single centre study from the USA, 40
of 426 liver transplants involved donor livers with at
least 30% microvesicular steatosis were compared
to the 386 livers without steatosis [8] The rates of
PNF (5.0% and 5.1%) were identical irrespective of
allograft microvesicular fatty deposition, although
there was a tendency for more prolonged
postoperat-ive ‘early poor graft function’ in the study group
One-year patient survival (80% compared to 79.8%)
and graft survival (72.5% compared to 68.4%) were
similar in both groups
Donor selection in relation to donor liver
fat content
There is no consistent threshold of estimated
macro-vesicular fat deposition above which liver
transplanta-tion is precluded Practices regarding acceptance of
donor livers with fat accumulation vary considerably
between surgeons In the study of the attitudes of liver
transplant surgeons to donor liver fat content cited
above, 27% of surgeons surveyed would
automatic-ally reject a liver with an estimated 30% steatosis
Seventy-six per cent of surgeons would decline the
offered liver that was thought to contain greater than
50% steatosis [5] Interestingly, 50% of the surveyed
surgeons considered microvesicular steatosis to be a
risk factor for PNF in the allograft (see above)
Risk factors such as diabetes mellitus in the donor
or poor health in the recipient may influence the
out-come of transplantation Thus, whereas livers with
more than 60% macrosteatosis should probably be
excluded automatically, livers with more moderate
steatosis (30 – 60%) may be utilized in the absence of
additional risk factors in the donor or recipient, or
when the recipient’s circumstances are judged to be
sufficiently critical to justify the risk [9]
Mechanisms of primary non-function or poor early
graft function
The mechanisms whereby steatosis of the donor organ
leads to PNF are not understood completely, but
several have been proposed [9,10]:
1 Diminished portal blood flow In animal studies,
hepatocytes ballooned with macrovesicular steatosis
distort the sinusoidal lumen and lead to increased
hepatic portal resistance, reduced blood flow and
secondary ischaemia
2 Inefficient anaerobic metabolism Fatty livers have
a relative increase in uncoupling protein levels withdecreased mitochondrial adenosine triphosphate (ATP)production [11] This is compounded during the ana-erobic phase of warm ischaemia and cold preservation.The energy level within the hepatocyte has been shown
to correlate with the eventual outcome after plantation [12]
trans-3 Physical properties of lipid Some studies suggest
that the sinusoids of steatotic livers have altered plasmamembrane fluidity, leaving them prone to increasedKupffer cell adhesion and activation on reperfusion [13].Alternatively, it has been hypothesized that the lipidsolidifies during cold preservation, causing physicaldisruption to the hepatocytes
4 Oxidative stress The steatotic liver is believed to
be prone to oxidative stress at baseline [14] Oxidativestress is a key component to reperfusion injury of the newly perfused graft One could speculate that
a steatotic liver already predisposed to oxidative stress would suffer greater injury at reperfusion than
a non-steatotic liver which is more able to maintainredox balance Indeed, administration of tocopherol,
an oxygen radical scavenger, improves survival ofZucker rats exposed to ischaemia and reperfusioninjury [15]
Living donor liver transplantation
In recent years, living donor liver transplantation bothfrom adult to child, and from adult to adult has beenadopted as a means to avoid death on the liver trans-plant waiting list and to improve overall outcomes [16].Given the small graft size, the need for rapid regenera-tion of liver volume in both the donor and recipientand the importance of avoiding morbidity in the donor,most centers aim to select donors with less than 10%steatosis and are reluctant to use livers with more than20% steatosis [17,18] Many centers exclude potentialdonors with a body mass index (BMI) > 28 MRI isbecoming the preferred method of detecting steatosis
as it allows for estimation of the quantity of fat present[19] Alternatively, an unenhanced computerized tomo-graphy (CT) scan of the liver showing the attenuation
of the liver to be at least 10 Hounsfield units less thanthe spleen is highly suggestive of fatty liver [19] Thus,potential donors with these findings can be excludedfrom liver donation without being exposed to the risk
of liver biopsy
Trang 17NAFLD and NASH as causes of end-stage
liver disease leading to transplantation
It has been recognized for some time that obesity is
an independent risk factor for end-stage liver disease
and for cirrhosis in patients with HCV infection [20]
or alcoholic liver disease [21,22] Furthermore, obesity
may accelerate the progression to liver failure in a
broad spectrum of liver disease patients Thus, 54%
of patients undergoing liver transplantation in one
North American series were overweight or obese [23]
Although a minority of these recipients were morbidly
obese, short- and long-term morbidity and mortality
were increased significantly in the obese group Much
of the increased late mortality is caused by increased
cardiovascular death
The prevalence of NAFLD or NASH among patients
with cirrhosis leading to liver failure in the absence
of chronic viral hepatitis, alcoholism or other
defin-able cause (cryptogenic cirrhosis) has been studied
only recently Nevertheless, although circumstantial,
an ever-increasing body of evidence suggests that
NASH can progress to end-stage liver disease A single
center study [24] noted that 2.9% of their primary
liver transplants were performed for NASH However,
they did not include patients who carried the diagnosis
of cryptogenic cirrhosis In 2002, approximately 7% of
US patients undergoing OLT had cryptogenic cirrhosis
as the aetiology of their liver disease [1] Recent studies
suggest that up to 50% of cases identified as
crypto-genic cirrhosis may in fact have arisen from NASH
[25,26] The prevalence of the insulin resistance
syn-drome (also known as the metabolic synsyn-drome) is
increased in patients given the diagnosis of cryptogenic
cirrhosis In two case–control studies of 70 [26] and 65[25] patients, respectively, obesity (defined as BMI> 31[26] or BMI> 30 [25]) and diabetes were considerablymore common among patients with cryptogenic cirrhosisthan among cirrhotic controls or the general popula-tion (Table 17.1)
Impact of the insulin resistance or metabolicsyndrome on selection of liver transplant candidates
It is likely that many potential transplant candidateswith cryptogenic cirrhosis are excluded because of thecomorbid impact of the insulin resistance syndrome[28] Nevertheless, drawing from available data, onecan make some estimates of the potential contribution
of NASH to the pool of patients in need of liver plantation in the next few years We start with the presumption that 3% of the normal population and20% of the obese population have NASH [29 –31] Wethen conservatively estimate that 15% of these personsare likely to progress to cirrhosis [32] The Centers forDisease Control (CDC) estimate that the prevalence
trans-of overweight and obesity will increase to 65% and30% respectively in the next 20 years, which wouldtranslate to a prevalence of 25 million patients withNASH and 3.7 million with cirrhosis This prevalencewould exceed by 10-fold the current USA prevalence ofHCV of 2.7 million and approximately 400 000 cases
of HCV-related cirrhosis
Impact of the insulin resistance syndrome onmorbidity and mortality after liver transplantationThere are no data directly addressing the impact of the insulin resistance syndrome on outcome after liver
Table 17.1 Prevalence of obesity and diabetes in patients with cryptogenic cirrhosis awaiting liver transplantation.
Prevalence of obesity (%)† Diabetes (%)‡
Study reference Cases Controls* Cases Controls Gen pop Cases Controls Gen pop
* Controls for Caldwell et al [26] exclude those with diagnosis of NASH.
† Obesity defined as BMI> 31.1 (males), > 32.3 (females) (Caldwell et al [26]), BMI > 30 (Poonawala et al [26]).
‡ Overall prevalence of diabetes in USA is 6.2%, but 20% in those over 65 years of age [27].