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ONCOLOGY LETTERS 8: 1810-1814, 20141810

Abstract. The current study presents a case of persistent

hypoglycemia as the initial manifestation of advanced

hepatocellular carcinoma (HCC), as well as a systematic

review of the management of hypoglycemia associated

with HCC. A 42-year-old female presented with loss of

consciousness and a blood glucose level of 30 mg/dl (normal

range, 80-140 mg/dl). Abdominal ultrasound and computed

tomography were performed to investigate tenderness in

the right upper quadrant, and the results revealed a hepatic

mass of 15 cm in diameter, with metastasis. A diagnosis of

insulinoma was ruled out by examining the insulin level.

Prednisolone treatment was ineffective for relieving thepersistent hypoglycemia, however, a single dose of pallia-

tive radiotherapy reduced the hypoglycemic episodes to

once monthly. Due to the advanced disease, the patient

refused further treatment, with the exception of a pallia-

tive therapy with glucose uid. The patient succumbed to

pneumonia with sepsis. A systematic review of the literature

indicated that steroids were the most commonly used drug

for hypoglycemia associated with HCC, however, in the

majority of cases no effect was noted as observed in this

study. Cytoreduction by surgery or systemic chemotherapy

has been the most effective treatment. Although rare, hypo-

glycemia may be the initial symptom of HCC. Cytoreductionis the most effective method of treating hypoglycemia asso-

ciated with HCC.

Introduction

Hypoglycemia has been reported to occur in 4-27% of

patients with hepatocellular carcinoma (HCC), and is associ-

ated with an unfavorable prognosis and poor survival (1). In

total, ~23% of cases of non-islet cell tumor hypoglycemia

(NICTH) are associated with HCC (2), typically appearing

during the nal stage of the disease (3). Although hypogly-

cemia associated with HCC is a recognized disease entity,

there is currently a lack of effective treatment or prevention.

The aim of the current study was to present a case of

HCC with hypoglycemia as the initial manifestation, and toperform a systematic review of the literature, with a focus on

treatments other than glucose infusion and frequent feeding.

Patient provided written informed consent.

Case report

In November 2010, a 42-year-old female presented to the

Emergency Department of the Shuang Ho Hospital, Taipei

Medical University (Taipei, Taiwan) due to loss of conscious-

ness. Once consciousness had been regained, the patient

reported no symptoms other than malaise and poor appetite

during the previous week, and denied any recent alcoholconsumption. No other medical history was reported, with

the exception of depression. A physical examination revealed

only right upper abdominal discomfort.

In the Emergency Department, the patient's vital signs

were as follows: Body temperature, 39.2˚C; blood pressure,

114/60 mm Hg; heart rate, 82 beats/min; and respiratory rate,

14 breaths/min. The patient's Glasgow Coma Scale score was

E4V1M4 (4). Laboratory testing revealed a blood glucose

level of 30 mg/dl (normal range, 80-140 mg/dl), a white blood

cell count of 11,800/µl (normal range, 4,800-10,800 /µl; 82%

neutrophils), a serum glutamic oxaloacetic transaminase

level of 108 IU/l (normal range, 5-40 IU/l) and a serum

glutamic pyruvic transaminase level of 74 IU/l (normal

range, 5-40 IU/l). The hepatitis B surface antigen level

was markedly elevated (6,216 index) and the test for the

Persistent hypoglycemia as an early, atypical presentation of

hepatocellular carcinoma:

A case report and systematic review of the literature

CHEN-YEN TSAI1, SHOU-CHU CHOU1, HSIEN-TA LIU1,2,3, JIUNN-DIANN LIN4 and YING-CHIN LIN1,3

1Department of Family Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei 23561; 2Graduate Institute of

Clinical Medicine, Chang Gung University, Tao‑Yuan 33302; 3Department of Family Medicine, School of Medicine,

College of Medicine, Taipei Medical University, Taipei 11031; 4Department of Endocrinology and Metabolism,

Shuang Ho Hospital, Taipei Medical University, New Taipei 23561, Taiwan, R.O.C.

Received January 7, 2014; Accepted June 12, 2014

DOI: 10.3892/ol.2014.2365

Correspondence to: Dr Ying-Chin Lin, Department of Family

Medicine, Shuang Ho Hospital, Taipei Medical University,

291 Zhongzheng Road, Zhonghe, New Taipei 23561, Taiwan, R.O.C.

E-mail: [email protected]

Key words: hypoglycemia, hepatocellular carcinoma, review,

steroids, signs and symptoms

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TSAI et al: HCC-INDUCED HYPOGLYCEMIA 1811

hepatitis C virus antibody was negative. Lumbar puncture

and drug levels excluded drug effects and central nervous

system infection. The initial diagnosis was hypoglycemia

and hepatitis B infection.

The patient was admitted, and electroencephalography

and brain magnetic resonance imaging revealed no signi-

cant findings. The patient's insulin level was <0.5 IU/ml(normal range, 3.0-25.0 IU/ml), while the blood glucose

level was 74 mg/dl, thus excluding a diagnosis of insuli-

noma. A diagnosis of NICTH was subsequently considered.

Abdominal ultrasound revealed a mixed echoic hepatic

tumor with ill‑dened margins (Fig. 1A), and abdominal

computed tomography revealed a large mass in the liver with

local metastasis (Fig. 1B and C). The serum α-fetoprotein

level was elevated (469,013 ng/ml; normal range, <20 ng/ml)

and the C-peptide concentration was reduced (0.06 ng/ml;

normal range, 0.81-3.85 ng/ml). Therefore, a diagnosis of

HCC and NICTH was formed.

Due to the advanced disease stage, the patient refused

active treatment and subsequently received only pa lliative

treatment, including prednisolone for the prevention of hypo-

glycemia. Following discharge, the patient presented to the

Emergency Department approximately twice a month due

to an altered level of consciousness. For these episodes, the

patient received a 50% dextrose infusion to relieve the persis-

tent hypoglycemia, followed by a 10% dextrose infusion to

maintain glucose homeostasis. In September 2011, a single

dose of palliative radiotherapy (5,000 cGy of 22 fractions)

for one month reduced the hypoglycemic episodes to oncemonthly. The patient was hospitalized with pneumonia in

January 2012. One week later this progressed to sepsis and

the patient succumbed.

Discussion

A search of the literature was conducted using Medline

(www.ncbi.nlm.nih.gov/pubmed), Cochrane (www.thec-

ochranelibrary.com/view/0/index.html), EMBASE (www.else-

vier.com/online-tools/embase) and Google Scholar (scholar.

google.com) on June 30, 2013, using combinations of the

following keywords: ‘Hepatocellular carcinoma’, ‘hepatoma’,

‘hypoglycemia’ and ‘hypoglycemic’. The inclusion criteria

were as follows: i) Primary HCC; ii) hypoglycemia considered

as a paraneoplastic symptom, not an adverse event of anticancer

Figure 1. (A) Abdominal ultrasound images revealing a large (>12 cm) mixed echoic hepatic tumor, with ill‑dened margins. Computed tomography scans

revealing (B) a large hepatic adenoma, with multiple daughter nodules, and (C) multiple daughter nodules in the right lobe of the liver on the coronal view.

Figure 2. Flow diagram of study selection.

A B C

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T a b l e I . S u m m a r y o f t h e s t u d i e s i n c l u d e d i n t h e s y s t e m a t i c r e v i e w .

A g e ,

y e a r s /

F i r s t a u t h o r / s , y e a r ( r e f . )

g e n d e r

T r e a t m e n t r e g i m e n f o r h y p o g l y c e m i a a

R e s p o n s e t o t r e a t m e n t

M c F a d z e a n

a n d Y e u n g , 1 9 5 6 ( 5 )

- / - b

2 0 0 m g c o r t i s o n e d a i l y

C o r t i s o n e h a d n o e f f e c t i n o n e p a t i e n t ; i n t w o p a t i e n t s , t h e g l u c o s e l e v e l

i n c r e a s e d , b u

t w i t h d r a w a l o f c o r t i s o n e r e s u l t e d i n r e t u r n o f h y p o g l y c e m i a

K l e i n a n d K

l e i n , 1 9 5 9 ( 6 )

6

2 / F

2 0 0 m g c o r t i s o n e d a i l y

N o b e n e c i a l e f f e c t

S c h o n f e l d e t a l , 1 9 6 1 ( 7 )

2 7 / M

6 0 m g m e t h y l p r e d n i s o l o n e d a i l y

N o e f f e c t

W i n g e t a l ,

1 9 9 1 ( 8 )

3 0 / M

8 u n i t s g r o w t h h o r m o n e , i n t r a m u s c u l a r l y

A t 3 0 m i n a f t e r d i s c o n t i n u a t i o n o f t h e g l u c o s e i n f u

s i o n , t h e d e c r e m e n t a l

e v e r y 8 h f o r t w o d a y s

c h a n g e i n b l o o d g l u c o s e l e v e l w a s ‑ 2 . 8 m m o l / l ; a t

6 0 m i n a f t e r t h e r a p y

w i t h g r o w t h h o r m o n e o r p r e d n i s o l o n e , t h e d e c r e m

e n t a l c h a n g e w a s

a t t e n u a t e d t o

- 1 . 2 m m o l / l

W i n g e t a l ,

1 9 9 1 ( 8 )

2 7 / M

1 m g / k g / d a y p r e d n i s o l o n e , o r a l l y f o r t w o d a y s

A t 3 0 m i n a f t e r d i s c o n t i n u i n u a t i o n o f g l u c o s e i n f u

s i o n , t h e d e c r e m e n t a l

c h a n g e i n b l o o d g l u c o s e l e v e l w a s 3 . 2 m m o l / l ; a t 6 0 m i n a f t e r t h e r a p y

w i t h g r o w t h h o r m o n e o r p r e d n i s o l o n e , t h e d e c r e m

e n t a l c h a n g e w a s

a t t e n u a t e d t o

- 1 . 5 m m o l / l

Y o n e i e t a l

, 1 9 9 2 ( 9 )

6 2 / M

G l u c a g o n , o r a l p r e d n i s o l o n e o r c h e m o t h e r a p y

N o t e f f e c t i v e

o r o n l y a t r a n s i e n t e f f e c t

( A d r i a m y c i n a n d c i s p l a t i n )

H o f a n d V a

s s i l o p o u l o u - S e l l i n , 1 9 9 8 ( 1 0 )

3

4 / M

D i a z o x i d e


S a i g a l e t a l , 1 9 9 8 ( 1 )

2 4 / F

P e r c u t a n e o u s e t h a n o l i n j e c

t i o n ( w e e k l y ) f o r

H y p o g l y c e m i c a t t a c k s b e c a m e i n f r e q u e n t a n d t h e i n t r a v e n o u s g l u c o s e

t h r e e c y c l e s

r e q u i r e m e n t m a r k e d l y d e c r e a s e d

T h i p a p o r n e t a l , 2 0 0 5 ( 1 1 )

3 6 / M

4 0 m g / d a y p r e d n i s o l o n e , f o l l o w e d b y

N o h y p o g l y c

e m i a o n d e x a m e t h a s o n e p r o v i d e d t h e

p a t i e n t r e c e i v e d

2 m g / d a y d e x a m e t h a s o n e

f o o d a t m i d n i g h t ; o n e m o n t h o f f o l l o w ‑ u p

N i k e g h b a l i a n e t a l , 2 0 0 6 ( 1 2 )

7 7 / M

C o m p l e t e s u r g i c a l r e m o v a

l o f t h e t u m o r

H y p o g l y c e m i a r e s o l v e d

K a m p i t a k , 2 0 0 8 ( 1 3 )

1 6 / M

S y s t e m i c c h e m o t h e r a p y w

i t h d o x o r u b i c i n

T e m p o r a r y r e s o l u t i o n o f h y p o g l y c e m i a

M a t s u y a m a

e t a l , 2 0 1 1 ( 1 4 )

6

9 / M

D e x a m e t h a s o n e


a A l l p a t i e n t s

r e c e i v e d g l u c o s e a n d f e e d i n g . b T h r e e p a t i e n t s s t u d i e d ; a g e / g e n d e r n o t d i s c l o s e d . F , f e m a l e ; M , m a l e .

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TSAI et al: HCC-INDUCED HYPOGLYCEMIA 1813

treatment; and iii) study published in the English language.

Studies that did not report the management of hypoglycemia,

or review articles and editorials were excluded.

Studies were identied according to this search strategy,

used by two independent reviewers. Where there was

uncertainty with regard to eligibility, a third reviewer was

consulted. The reference lists of the relevant studies were

also searched. The following information and results wereextracted from the studies that met the inclusion criteria: The

name of the rst author, year of publication, study design,

number of subjects, patient age and gender, and treatment

regimen for hypoglycemia other than glucose infusion,

feeding or supportive care.

A total of 108 potentially relevant studies were identi-

ed by the initial review, and following the application of

the inclusion and exclusion criteria, 11 studies remained for

inclusion in the systematic review. A ow diagram of the

study selection is shown in Fig. 2, and the 11 included studies

(1,5-14) are summarized in Table I. Steroids were the most

commonly used drug for the management of hypoglycemia;

however, in the majority of cases, no effect, or only a transient

effect with respect to increasing glucose levels, was noted.

In one case, growth hormone was administered (8 units

intramuscularly every 8 h) and although the glucose levels

increased, the hypoglycemia was not resolved (8). Diazoxide

was used in another case, but no beneficial effect was

noted (10). Cytoreduction by surgical removal of the tumor

resulted in resolution of the hypoglycemia in one case (12),

while percutaneous ethanol injection of the tumor resulted

in the resolution of the hypoglycemia in another case (1).

Furthermore, systemic chemotherapy resulted in a transient

resolution in one case (9).

Paraneoplastic manifestations of hypoglycemia commonlyoccur in association with large abdominal tumors; however,

hypoglycemia is a rare initial presentation of HCC. Patients

with hypoglycemia and HCC have low concentrations of

insulin and C-peptide (15), which rules out insulin overpro-(15), which rules out insulin overpro-which rules out insulin overpro-

duction as a cause.

Two types of hypoglycemia have been associated with

HCC (16). Type A hypoglycemia occurs in end-stage HCC,

with rapid tumor growth, and once hypoglycemia occurs,

mortality may occur within two weeks (3,17). Hypoglycemia

is typically mild and is caused due to the inability of a severely

damaged liver to meet the body's demand for glucose (3,17).

Type B hypoglycemia, as observed in the present case, accom-panies slow-growing tumors, usually occurs between two and

10 months prior to mortality and is severe (3,17). Patients

typically present with marked alterations in consciousness,

convulsions or coma. Type B hypoglycemia is considered to be

due to the defective processing of the precursor to insulin-like

growth factor II by tumor cells. The defective precursor passes

more easily across capillary membranes, resulting in increased

glucose uptake (3,15,17).

Surgical excision and chemotherapy may effectively reduce

the tumor volume and relieve hypoglycemia (18). However,

a large tumor volume usually precludes tumor resection in

type B hypoglycemia. Frequent feeding, parenteral dextrose

infusion, corticosteroids and growth hormones have all been

used for the management of hypoglycemia with varying

degrees of success (3).

The results of the systematic review presented in the

current study suggested that the most effective management

for hypoglycemia resulting from HCC is cytoreduction by

surgery (18), chemotherapy (13) or ethanol injection, as

described by Saigal et al (1). In the present patient case,

cytoreduction by radiotherapy was also effective in reducing

the frequency of the hypoglycemic episodes. However, in the

majority of cases, cytoreduction is not an option due to theterminal condition at diagnosis. No effective and convincing

pharmaceutical treatments were noted from the literature

review. Steroids were the most frequently used drug for the

management of hypoglycemia resulting from HCC, however,

the results were mixed. A long-acting steroid accompanying a

midnight meal appeared to be more effective than short-acting

steroids, however, the effect was transient (11).

The span of the publication of the 11 studies ranged between

1956 and 2011, and during that period of time diagnostic modali-

ties and treatments have changed greatly. Although accurate

diagnostic tools and interventions for HCC now exist, and the

mechanism of the hypoglycemia resulting from HCC has been

characterized, the results of the review indicate that effective

management for hypoglycemia resulting from HCC is lacking.

In conclusion, NICTH must be considered when evalu-

ating patients with persistent hypoglycemia, and although

rare, hypoglycemia may present as an initial symptom of

HCC. Cytoreduction is the most effective method for treating

hypoglycemia associated with HCC, and while steroids are

frequently used, they are not effective in the majority of cases.

References

1. Saigal S, Nandeesh HP, Malhotra V and Sarin SK: A case of

hepatocellular carcinoma associated with troublesome hypo-glycemia: management by cytoreduction using percutaneousethanol injection. Am J Gastroenterol 93: 1380-1381, 1998.

2. Kahn CR: The riddle of tumour hypoglycaemia revisited. ClinEndocrinol Metab 9: 335-360, 1980.

3. Yeung RT: Hypoglycemia in hepatocellular carcinoma: a review.Hong Kong Med J 3: 297-301, 1997.

4. The Brain Trauma Foundation. The American Association ofNeurological Surgeons. The Joint Section on Neurotrauma andCritical Care. Glasgow coma scale score. J Neurotrauma 17:563-571, 2000.

5. McFadzean AJ and Yeung TT: Hypoglycemia in primarycarcinoma of the liver. AMA Arch Intern Med 98: 720-731, 1956.

6. Klein H and Klein SP: Spontaneous hypoglycemia associatedwith massive hepatoma; a review of current concepts and reportof a case. AMA Arch Intern Med 103: 273-278, 1959.

7. Schonfeld A, Babbott D and Gundersen K: Hypoglycemia andpolycythemia associated with primary hepatoma. N Engl JMed 265: 231-233, 1961.

8. Wing JR, Panz VR, Joffe BI, Kalk WJ, Seftel HC, Zapf J andKew MC: Hypoglycemia in hepatocellular carcinoma: failure ofshort-term growth hormone administration to reduce enhancedglucose requirements. Metabolism 40: 508-512, 1991.

9. Yonei Y, Tanaka M, Ozawa Y, Miyazaki K, Tsukada N, Inada S,Inagaki Y, Miyamoto K, Suzuki O, Okawa H, et al: Primary hepa-tocellular carcinoma with severe hypoglycemia: involvement ofinsulin-like growth factors. Liver 12: 90-93, 1992.

10. Hoff AO and Vassilopoulou-Sellin R: The role of glucagonadministration in the diagnosis and treatment of patients withtumor hypoglycemia. Cancer 82: 1585-1592, 1998.

11. Thipaporn T, Bubpha P and Varaphon V: Hepatocellularcarcinoma with persistent hypoglycemia: successful treatmentwith corticosteroid and frequent high carbohydrate intake. J Med

Assoc Thai 88: 1941-1946, 2005.12. Nikeghba lian S, Bana nzadeh A a nd Yarmoham madi H:

Hypoglycemia, the first presenting sign of hepatocellularcarcinoma. Saudi Med J 27: 387-388, 2006.

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13. Kampitak T: Successful treatment of non-islet cell tumorhypoglycemia in hepatocellular carcinoma with doxorubicin.Cancer Chemother Pharmacol 62: 929-930, 2008.

14. Matsuyama M, Sugiura S, Kakita A, Sato Y and Kuroda M:Hepatocellular carcinoma arising f rom ectopic liver tissue inthe spleen producing insulin-like growth factor II. Pathol ResPract 207: 124-126, 2011.

15. Benn JJ, Firth RG and Sönksen PH: Metabolic effects of aninsulin-like factor causing hypoglycaemia in a patient with ahaemangiopericytoma. Clin Endocrinol (Oxf) 32: 769-780, 1990.

16. McFadze an AJ a nd Yeung RT: Fur ther ob servat ions onhypoglycaemia in hepatocellular carcinoma. Am J Med 47:220-235, 1969.

17. Di Bisceglie AM: Malignant neoplasms of the liver. In:Schiff's Diseases of the Liver. Schiff ER, Sorrell MF andMaddrey WC (eds). 8th edition. Lippincott-Raven, New York,NY, pp1288-1289, 1999.

18. Le Roith D: Tumor-induced hypoglycemia. N Engl J Med 341:757-758, 1999.

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