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Functional recovery after liver resection

Veteläinen, R.L.

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Citation for published version (APA):Veteläinen, R. L. (2006). Functional recovery after liver resection

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Download date: 28 May 2018

CL L a a SZ SZ u u

Reetaa Vetelainen

Dehaa Erdogan

Wilmarr de Graaf

Fiboo ten Kate

Peterr LM Jansen

Dirkk J Gouma

Thomass M van Gulik

hJ^l-^maa a

Introduction n < <

Hepatocellularr adenoma (HCA) is a benign solitary liver lesion which mostly occurs in young Ui

w o m a nn w i th a history of oral contraceptive use (OCC) and cessation of OCC may regress the nodule fD

sizee (1,2,3). Flejou et al def ined liver adenomatosis (LA) as the presence of multiple (arbitrary >10), o

adenomass scattered throughout normal liver parenchyma in a patient w i th no history of steroid g

therapyy or glycogen storage disease (4,5). Contradictory to Flejou, recent reports show female £

predominancee and relation w i th OCC (6,7). —*

Clinicall presentation of LA relates to the size of the largest nodule causing abdominal symptoms 5 *

(4).. Larger nodules of ten present wi th intralesional haemorrhage that may rupture w i th in the j£

peritoneall cavity (6,8). In literature, the preferred management for symptomatic patients is £2

resectionn of the larger tumor(s) (2,6,9). The potential risk of malignant transformation has also 2

warrantedd orthotopic liver transplantation as the recommended treatment (2,4). Recent reports,

however,, favor a more conservative approach and surgery is recommended for more aggressively

growingg lesions (5,7). In addition, less invasive embolization methods has been proposed. However,

duee to the rarity of the disease, the optimal management and prognosis remain unclear and there

aree no established guidelines for the management of patients wi th LA.

Diseasee etiology is also uncertain which hampers effective therapy of this disease. A recent study

reportss the presence of nonalcoholic steatohepatitis in a patient w i th LA (10) and there is also

growingg evidence of a connection between altered glucose metabolism and LA through germline

mutationss in hepatocyte nuclear factor (HNF) -1a (11,12). As altered glucose metabolism and

nonalcoholicc fat ty liver disease (NAFLD) are closely connected, a relationship between LA and

NAFLDD is also possible. The main focus of this study is to identify novel features associated w i th

LAA that may have impact on surgical management and the short and long-term prognosis of these

patients.. We also discuss innovative treatment strategies potentially applicable to patients wi th LA.

Materialss and methods

Thee patient database of Academic Medical Center (AMC) in Amsterdam between 1997 and

20066 was analyzed . For the definition of LA, the presence of multiple hepatic (>10) nodules and

thee exclusion of patients with glycogen storage disease or previous steroid therapy was used.

Thee definitive diagnosis was based on imaging studies and/or histopathology by an experienced

pathologist.. Furthermore, clinical status, laboratory and radiological evaluation, histopathology,

surgicall management and outcome were reviewed. All published case reports and series were

reviewedd and analyzed in detail (1-12, 14-44). A search in the Medline (1 January 1963 to January

2006)) was performed using MESH terms liver adenoma and liver adenomatosis. Patients from

ourr own series and from the literature were combined and analyzed by commercial computer

packagee (SPSS 10.1.).

163 3

Results s

Demographics s

Sixx patients were referred to the AMC in the period 1997-2006 (Table 1). All referred patients

weree female and the mean age at the time of the diagnosis of LA was 39.6 years (range 32-50).

Alll patients had a history of OCC use for periods ranging from 4-20 years; in three patients, the

precisee length of OCC use was uncertain. Medical history was negative for glycogen storage

diseasee or any previous steroid therapy. Two patients had diabetes (type II) diagnosed either

shortlyy before or at the time of LA diagnosis.

Tablee 1. The patient series

Sex/Age e

OCCC use

Clinical l manifestations s

Serum m

CEA,, a-FP

Ultrasound d

CT T

Diagnosis s

Complications s

Tumorr size

Additional l histology y

Treatment t

F-32 2

100 y

abdominal l discomfort t

ALTT 1.5N, t-Bil2N N

negative e

multiple e

hypodense e lesions s

hypodense e inn AP

laparoscopy, , biopsy y

intratumoral l bleeding g

11.55 cm

severe e microvesicular r

steatosis s

rightt hemi-hepatectomy y

F-42 2

200 y

chronic c abdominal l painn for 5 y

AST21N, , ALTT 29N. t-Bill 1.5N

negative e

multiple e hypodense e lesions s

hyperdense e inn AP

CT T

intratumoral l bleeding g

7.44 cm

diffuse e hepatic c steatosis s

conservative, , afterr 12

F-36 6

yes s

acute e abdominal l pain n

ASTT 2N, ALT N

negative e

unspecific c

isodensee in AP

laparoscopy. . biopsy y

intraperitoneal l bleeding g

100 cm

macrovesicular r

steatosiss in nodules,, FNH

1.. resection of

extrahepatic c

F-44 4

Yes s

acute e abdominal l pain n

AST20N, , ASTT 16N, t-Bill 1.5N

negative e

unspecific, , subcapsular r hematoma a

hyperdense e inAP P

US-guided d biopsy y

subcapsular r hematoma a

44 cm

No o

conservative e

F-34 4

4y y

painn in left flank

ASTT N, ALT N

negative e

multiple e hyperdense e lesions s

hyperdense e inAP P

laparoscopy, , biopsy y

no o

4.44 cm

steatohepatitis, , FNH H

segmentt VI resection n

F-50 0

yes s

incidental l

ASTT N, ALT N

negative e

multiplee pain hyperdense e lesions s

hyperdense e inAP P

US-guided d biopsy y

intratumoral l necrosis s

3.55 cm

severe e steatosis s

conservative e

monthss HAE tumor 2.. segment V resection n

Outcome e Welll after 6 months, , noo tumor growth h inCT T

Welll after 12 months, , noo tumor growth h inCT T

Welll after 8 years,, tumor growthh in CT

Welll after Well after 25 244 months, months, noo tumor no tumor growthh growth inn CT In CT

Welll after 30 months,, tumor regression n inCT T

t-Bil== plasma total bilirubin, AP = arterial phase of contrast CT, FNH= focal nodular hyperplasia, HAE= hepatic arteryy embolization

164 4

Diagnosticc modalities

Elevationn of liver enzymes and bilirubin was seen in four patients of our own series (table 1). In

alll patients, blood coagulation values were normal and tumor markers (CEA, a-fetoprotein) and

hepatitiss markers (B, C) negative. Five patients were symptomatic at the time of the LA diagnosis. In

patientt 6, LA was incidentally diagnosed during US-examination performed in relation with severe

obesitas.. One patient presented with an unspecific abdominal swelling and others with acute pain

inn the left flank, right epigastric area or unspecifically in the abdomen. The size of the largest tumors

rangedd from 3.5 cm to 11.5 cm without a direct relation with the severity of the symptoms as the

patientt with the largest single tumor had only abdominal discomfort and no actual pain.

Abdominall US was the initial imaging modality applied in all patients, followed by contrast-

enhancedd CT. The presentation of nodules in US and CT is summarized in Table 2. In patient

1,, US-guided liver biopsy was suspicious of hepatocellular carcinoma but additional diagnostic

laparoscopyy with a new biopsy was negative for malignancy. In patients 5 and 6, US-guided

biopsyy was performed and histopathology was typical of HCA, without signs of malignancy.

Additionally,, 99mTc-RBC scintigraphy was performed in patient 1, because unclear diagnosis

afterr US, CT and US-guided biopsy. Scintigraphy showed atypical findings for hemangioma; a

malignancyy could not be excluded.

< < O O T T P P Q. Q. O O 3 3 O O

P P r t t O O 1/1 1

C C

Tablee 2. Review of patient characteristics

Age e

Male e

Female e

OCC C Yes s

Tumorr characteristics

Primary y

symptoms s

Tumorr size

Bleeding g

N o / / incidental l

Acutee pain

Chronicc pain

Pain# #

Hepatomegaly y

Non-specific c

Gll -symptoms

Meann (range) (nn of patients)

No o

ITN N

ITB* *

IPB** *

94 4

34.0(12-75) )

12%% (11)

88%% (83)

52% % (43/83) )

26%% (24)

43%% (40)

16%% (15)

9%% (8)

31%% (29)

7%% (7)

47%% (44)

2%% (2)

26%% (24)

20%% (19)

21%% (20)

37.77 (14-75)

5%% (1)

95%% (19)

50%% (10)

25%% (5)

30%% (6)

25%% (5)

15%% (3)

40%% (8)

15%% (3)

3.6(2--4.5)09) )

65%% (13)

5%% (1)

20%% (4)

10%% (2)

53%% (51)

33.9(12--54) )

12%% (6)

88%% (45)

57%% (29)

22%% (11)

59%% (30)

6%% (3)

8%% (4)

20%% (10)

4%% (2)

7.8(5-15) ) (51) )

47%% (24)

2%(1) )

26%% (13)

26%% (13)

26%% (23)

32.3(13--

53) )

17%% (4)

83%% (19)

22%% (5)

35%% (8)

17%% (4)

35%% (8)

4%% (1)

48%% (11)

8%% (2)

unknown n

30%% (7)

28%% (7)

16%% (4)

25%% (24)

32.5(13--53) )

17%% (4)

83%% (20)

54%% (13)

100%% (24)

13%% (3)

5.4(3-8) )

(15) )

67%% (16)

4%(1) )

13%% (3)

8%% (2)

75%% (70)

34.77 (12-75)

10%% (7)

90%% (63)

44%% (31)

57%% (41)

23%% (16)

11%% (8)

37%% (26)

10%% (7)

7.0(2-15) ) (55) )

40%% (29)

3%% (2)

30%% (21)

24%% (17)

165 5

Variables s Totall Tumor size 1 Tumor J Unknown j Asymptomatic <5cm<5cm I size j j Symptomatic

53%% (51) 26% (23) 25% (24) 75% (70)

Age e

Male e

Female e

OCC C Yes s

Tumorr characteristics

Primary y

symptoms s N o / /

incidental l

34.0(12-75) )

12%% (11)

88%% (83)

52% % (43/83) )

26%% (24)

37.7(14-75) )

5%(1) )

95%% (19)

50%% (10)

25%% (5)

33.99 (12-54) )

12%% (6)

88%% (45)

57%% (29)

22%% (11)

32.33 (13-

53) )

17%% (4)

83%% (19)

22%% (5)

35%% (8)

32.5(13-53) )

17%% (4)

83%% (20)

54%% (13)

100%% (24)

34.7(12-75) )

10%% (7)

90%% (63)

44%% (31)

Managementt and Outcome

Surgicall treatment

Initiall management consisted of surgical resection of the largest lesion in three patients (patients 1,

33 and 5). In patient 1, preoperative right portal vein embolization (PVE) was performed to increase

remnantt liver volume in the presence of severe steatosis. Subsequently, right hemihepatectomy

extendedd with resection of half of segment 4a was performed without complications. In patient

3,, a LA lesion hanging from the liver was resected laparoscopically and was complicated by

bleeding.. At subsequent laparotomy, the largest nodule located in the segment 5 was resected

becausee of intended pregnancy. The patient has been asymptomatic during a follow-up time of

88 years; however, the size and number of nodules have slightly increased on CT. Also in patient

5,, the largest nodule located in segment 6 was resected without complications. Follow-up of 25

monthss has been uneventful and patient is pain-free.

Conservativee treatment

Initially,, three patients (patients 2, 4 and 6) were observed including cessation of OCC medication.

Inn patient 2, the diameter of the largest nodule had increased after 12 months on follow-up

CT.. Because the patient also had abdominal discomfort, percutaneous selective embolization of

thee nodule via the hepatic artery was undertaken. Follow-up of 12 months was uneventful and

noo change in nodule size or number were detected on CT. Patient 4 who presented with an

intrahepaticc bleeding was treated conservatively and after 2 months, resolution of a subcapsular

hematomaa was seen on CT with signs of recent bleeding. In addition, multiple lesions (0 2-4

cm)) were detected in segments 2-4. Follow-up was uneventful for 24 months and the patient is

currentlyy symptom-free. Patient 6 was observed and after withdrawal of OCC, reduction of lesion

sizee was observed. At 30 months after diagnosis of LA, no nodules were detected on CT.

Histopathology y

Inn all our patients the histopathology of the nodules met with the previously reported criteria

forr benign adenoma (13). All nodules showed cell plate 1-3 layers thick in the reticulin stain with

intactt reticulin pattern. The lesional hepatocytes showed cellular proliferation, variable sized and

double-formm nuclei most prominent in the largest nodules. In the nodules, the arterialization, small

arteries,, derived {CD-34 positive cells) from sinusoidal beds. The non-lesional hepatic parenchyma

showedd intact architecture with regular central veins and portal fields. In the portal fields and

aroundd central veins inflammatory cells with segment patterned nuclei were present.

Inn three patients, a resection specimen and in two patients, a representative needle biopsy was

availablee for histopathological evaluation. In patient 4, a biopsy obtained under US-guidance was

consideredd inadequate for reliable evaluation.

Inn patients 1 and 3, presenting with the largest tumors, i.e. 11.5 cm and 10 cm, respectively, the

tumorss were macroscopically encapsulated with intratumor necrosis. The smaller tumors were

mostlymostly encapsulated and well demarcated from the surrounding hepatic parenchyma.

Inn 4 patients, steatosis was present in the non-lesional hepatic parenchyma surrounding the

nodules.. In all patients steatosis was of the severe type, involving more than 60% of all hepatocytes.

Patientt 1 presented with severe, centrilobularly focated, mtcrovestcular steatosis, patient 3 with

severee macrovesicular steatosis and patient 6 with severe micro- and macrovesicular steatosis.. In

patientt 5, steatosis had developed into steatohepatitis with fibrosis. In addition, patients 3 and

55 had also a single FNH lesion among multiple LA nodules. The overall non-lesional parenchyma

showedd intact cellular architecture with regular central veins and portal fields in all patients.

Discussion n

Demographics s Wee report the largest review so far of 94 patients with LA collected to date, consisting of all

publishedd case reports and all small series including our own series (Table 2). Only descriptive data

analysiss was performed because of the heterogeneous source of data. Strong female predilection

inn incidence of LA suggested in literature was also seen in our review (6,7). Of all patients, 52%

off females had a history of OCC use. Eight patients were younger than 18 years and 12% were

malee (Table 2). As estrogen/progesterone-positive and negative receptors can be unevenly found

inn LA nodules, it seems that the role of exogenous estrogen is not important in induction of LA

butt might play a role in disease progression (5). In our analysis a slightly higher incidence of OCC

usee was seen in females with larger tumor sizes, i.e. > 5cm.

Etiology y Thee etiology of LA remains unclear and a variety of predisposing conditions have been suggested.

Congenitall or acquired hepatic vascular abnormalities tend to occur more often in patients with

FNHH and HCA. Of all patients, 8 had a concomitant single lesion of FNH and some presented with

co-extstingg vascular malformations suggesting some role for vascular abnormalities (6,7,23,29).

Thee first connection between LA and diabetes was reported in 1978 (19). Interestingly, 2 of our

ownn patients had diabetes {type II) diagnosed at the time of LA diagnosis. Unfortunately, diabetes

wass assessed only in few reviewed studies (10,11,12,19). Recent studies report a familial autosomal

transmissionn of LA in one family and a familial type of LA linked with germline mutations of HNF-1a

inn two families (6,12). These mutations are associated with a rare form of diabetes, a non-ketotic

typee present in patients younger than 25 years (11-12). HNF - la mutation could present a genetic

predispositionn and LA would develop in presence of another factor because the expression of

thee mutation phenotype was variable within the families (12). This can be a vascular anomaly or

somaticc mutation in another allele. Unfortunately, HNF - la detection by immunohistochemistry is

nott yet possible in paraffin-preserved tissue samples and therefore, this analysis was not possible

inn our own patient series.

Thee etiology of NAFLD has close connection with western lifestyle and is therefore considered

aa rising clinical challenge (45). An association between LA and NAFLD was recently suggested

(10).. Interestingly 18% of all LA patients had steatosis, varying from mild to steatohepatitis. In

ourr own series, 5 of 6 patients had steatosis along with LA. Three patients had histologically

confirmedd steatosis; one patient had severe macrovesicular, one severe microvesicular and one

hadd combined micro- and macrovesicular steatosis. In addition, one patient had diffuse steatosis

diagnosedd by US. Furthermore, one patient had steatohepatitis, which is second ever published

inn the literature (10).

LAA nodules typically show steatosis but it seems that the co-existence of non-tumoral steatosis

hass increased during the last years. This might in part be explained by increased risk factors for

steatosiss and recognition of steatosis as a potential risk factor in liver surgery. However, LA is

diagnosedd also in young, lean adults and children. Furthermore, the microvesicular type of steatosis

iss not commonly connected with obesity-related steatosis as opposed to the macrovesicular type.

Thee microvesicular steatosis is often seen in patients with more acutely induced steatosis, such as

byy toxins or drugs. Glycogen storage disease induces rapid and massive LA, presenting often in

childrenn younger than 5 years (2). Therefore, considering all these aspects, etiology of LA has a

potentiall connection to deranged hepatic glucose metabolism with a yet unknown mechanism.

Furtherr research is needed to unravel this aspect.

Thee diagnosis tntn 43% of all analyzed patients with LA (including the literature and our own series), clinical

presentationn was with acute pain. However, in contrast to previous reports, the diagnosis was

fortuitouss in 25% of patients. Early diagnosis is vital, as hemorrhage is a common complication

inn patients with LA. In literature, an overall bleeding rate from 46% to 63% is reported (4,5) In

ourr analysis, the overall bleeding rate was 46% and had in two cases led to death (6, 23). In

54%% of symptomatic patients, intraperitoneal or intratumoral bleeding was present at the time of

diagnosis.. The actual prevalence of hemorrhage is difficult to estimate as symptomatic patients

aree more likely to seek medical help thus creating a selection bias. However, of all asymptomatic

patientss with incidentally discovered LA, only 8% had intraperitoneal and 13% had intratumoral

bleeding. .

Inn patients with intra-abdominal bleeding, LA is diagnosed on CT or during emergency laparotomy.

However,, in less acute patients the diagnosis is more complicated. As seen in our series (Table

1)) and in literature, plasma liver enzymes are unreliable with poor correlation with LA. Most

symptomaticc patients presented with epigastric or abdominal pain or discomfort of acute or chronic

onsett (Table 2). Additional symptoms include gastrointestinal complaints and hepatomegaly

(4,6,32).. During diagnostic work-up, several differential diagnoses might emerge, because of

diversityy of the LA tissue components such as necrosis, fat, calcification and hemorrhage, present

ass a variety of hypo-, iso- and/or hyperdense radiological features. Grazioli et al concluded that

thee most useful method for initial diagnosis is multiphase-helical CT or MRI (7). Most adenomas

weree uniformly or heterogeneousiy hyperattenuatmg lesions during the arterial phase like in our

series.. However, noncontrast images are needed for identification of local fat and hemorrhage

andd portal phase images for evaluation of vascular anomalies (7). A potential modality to identify

co-existingg steatosis is nuclear magnetic resonance spectroscopy ('H-MRS) providing a sensitive

andd quantitative technique to measure intrahepatic fat content (46). The obvious advantage of

'H-MRSS is that it samples noninvasively a considerably larger liver volume than standard liver

biopsy.. With ^-MRS the analysis of various liver lobes and/or regions is also possible, diminishing

thee bias introduced by heterogeneity of distribution of hepatic fat (46,47).

Evenn though imaging is useful in lesion identification, the total number of lesions detected during

surgeryy is usually higher because of the extensive number of small adenomas usually scattered

throughoutt the liver (43). Together with multiphase-helical CT or MRI, histopathology of several

noduless should be the gold standard for definitive diagnosis of LA. Only single core biopsy of

onee nodule might be misleading or even non-diagnostic due to co-existing parenchymal diseases

and/orr to different lesion components. For an accurate diagnosis and a reliable exclusion of

malignancy,, several biopsies should be taken preferably during laparoscopy or laparotomy to

ensureensure the control of any bleeding. It should be taken into account that the bleeding risk after

singlee biopsy is 0.7% (49) and is likely higher in LA patients because of the hypervascular structure

off the nodules. Intratumoral bleeding was already present in 26% of all LA patients at the time

off diagnosis.

< < n n ? ?

v v a. a. n n o o 3 3 O O I/) )

CI I C C -: : O O 3 3

Managementt of LA

Inn figure 1 is summarized the suggested management of LA patients. In all management strategies,

aa close follow-up is necessary using CT or MRI even if clinical presentation does not require

invasivee management. Also, because of the unsolved issue of potential malignant transformation,

controll of «-fetoprotein levels should be added to the follow-up (2,5,7). In our patients no signs

forr malignant transformation could have been detected during follow-up. Surgical management

remainss complex, not only because of the large number of adenomas requiring major liver

Symptomat icc patients

Hemorrhage e Abdominall pain, Mechanicall complaints

1)) Hepatic artery embol izat ion

2)) Emergency laparotomy and packing g

Conservativee management

Asymptomat icc patients

Imaging g Sizee of largest nodule < 5 cm

Cessationn of OCC

Fol low-upp CT after 6 months, AFP P

Sizee of largest nodule > 5 cm

1)) Cessat ion of OCC 2)) Selective hepatic artery embol izat ion 3)) Resect ion of the largest nodule 4)) Transplantat ion (mult iple lesions,

aggressivee growth, severe symptoms)

Figuree 1. The proposed management strategy for asymptomatic and symptomatic patients with LA.

69 9

resectionn but also because of the risk of hemorrhagic complications during surgery. Large

adenomas,, particularly superficial, have a higher risk of bleeding with a mortality rate of 7%. In

emergency,, i.e. in case of rupture of the bleed into the peritoneal cavity, selective angiography of

thee hepatic artery with embolization is recommended (50). In case of extensive bleeding, either

excisionn of the bleeding tumor or packing has been recommended (12,44). In our review, an

equall number of symptomatic and asymptomatic patients were primarily resected (57% vs. 54%)

andd in both groups, an equal number of secondary interventions were performed (21% vs 17%).

Inn patients with tumors >5 cm, 59% was resected compared to 35% of smaller tumors. In larger

tumors,, secondary interventions were needed in 25% of patients vs. 8% if the size was less than

55 cm. However, 40% of smaller tumors continued to grow during follow-up. Interestingly, after

surgeryy in patients with tumors > 5 cm, the remaining tumors remained stable. Of all analyzed

patientss (94), tumor(s) showed regression during follow-up only in three patients.

Liverr resection should be considered when a nodule is larger than 5cm, if malignancy cannot be

ruledd out or when a larger nodule presents with severe pain. For the most aggressively growing

tumors,, OLT has been considered too (6,7). Still, a selection of patients can benefit from extensive

resectionn without any negative effect on outcome as we noticed no difference in the long-term

outcomee of conservatively or surgically treated patients. Resection can be preceded by PVE to

increasee the future remnant liver volume consequently decreasing the risk of postoperative liver

failuree and complications. However, as PVE increases hepatic arterial blood supply, an increase in

thee volume of hyperarterialized LA is possible, as found in our patient 1. Therefore, the addition

off sequential arterial embolization (TAE) or the combination therapy, i.e. TAE followed by

percutaneouss ethanol injections, might be preferred (51). In patient 4, an elective hepatic artery

embolizationn was sufficient to induce tumor regression.

Inn any patient with LA considered for liver resection, potentially co-existing steatosis should be

acknowledged.. This is because of the impact of liver steatosis on the outcome of liver surgery.

Evidencee is accumulating that all grades of steatosis, even the mildest, potentially affect the

recoveryrecovery of patients after transplantation and liver resection (52,53,54). It is noteworthy in this

connectionn that in our own series of 6 patients, 5 featured severe type of steatosis.

Conclusion n

LAA is a progressive, benign parenchymal disease mainly occurring in females. There is a potential

linkk with hepatic steatosis with implications for the management of patients with LA. Noninvasive

diagnosiss is difficult because of the variety of tissue components. Management should primarily

bee conservative with careful follow-up.

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