Study: HGH for High Liver values in Hep B peeps

Combined human growth hormone and lactulose for prevention
and treatment of multiple organ dysfunction in patients with
severe chronic hepatitis B
Hui-Guo Ding, Jing Shan, Bin Zhang, Hong-Bo Ma, Li Zhou, Rui Jin, Yu-Fen Tan, Li-Xiang He
ELSEVIER
PO Box 2345, Beijing 100023, China World J Gastroenterol 2005;11(19):2981-2983
www.wjgnet.com World Journal of Gastroenterology ISSN 1007-9327
wjg@wjgnet.com © 2005 The WJG Press and Elsevier Inc. All rights reserved.
Hui-Guo Ding, Jing Shan, Bin Zhang, Hong-Bo Ma, Li Zhou,
Rui Jin, Yu-Fen Tan, Li-Xiang He, Department of Gastroenterology
and Hepatology, Beijing Youan Hospital, Capital University of
Medical Sciences, Beijing 100054, China
Supported by the Foundation of Beijing Science and Technology
Commission, No. H010210110129
Correspondence to: Dr. Hui-Guo Ding, Department of
Gastroenterology and Hepatology, Beijing Youan Hospital, Capital
University of Medical Sciences, Beijing 100054,
China. dinghuiguo@medmail.com.cn
Telephone: +86-10-63292211-2718 Fax: +86-10-63295525
Received: 2004-03-05 Accepted: 2004-04-13
Abstract
AIM: To evaluate the efficiency and safety of combined
recombinant human growth hormone (rhGH) and lactulose
for treatment and/or prevention of multiple organ dysfunction
in patients with chronic severe hepatitis B.
METHODS: Forty-eight inpatients with chronic severe
hepatitis B were randomly divided into rhGH group (n = 28)
and control group (n = 20). In rhGH group, 4-4.5 IU of
rhGH was injected intramuscularly once daily for 2-4 wk,
and 100 mL of enema containing 30 mL of lactulose, 2 g
of metronidazole and 0.9% saline was administered every
2 d for 2-4 wk. Their symptoms and complications were
noted. Liver and kidney functions were analyzed by an
Olympus analyzer. Serum GH, IGF-1, IGFBP1 and IGFBP3
were measured by ELISA.
RESULTS: Clinical symptoms of 90% of these patients in
rhGH group were obviously improved. The total effectiveness
in rhGH group was better than that in control group
(75% vs 40%, P<0.05). After 2- and 4-wk treatment of
rhGH respectively, serum albumin (26.1±4.1 vs 30.2±5.3,
31.9±5.1 g/L), prealbumin (79.6±28.0 vs 106.6±54.4,
108.4±55.0 g/L), cholesterol (76.3±16.7 vs 85.6±32.3,
96.1±38.7 mg/dL), and IGFBP1 (56.8±47.2 vs 89.7±50.3
ng/mL after 2 wk) were significantly increased compared
to control group (P<0.05). However, serum GH was
decreased. The increase of serum IGF1 and IGFBP3 after
rhGH treatment was also observed.
CONCLUSION: rhGH in combination with lactulose may
be beneficial to the prevention and treatment of multiple
organ dysfunction in patients with chronic severe hepatitis.
© 2005 The WJG Press and Elsevier Inc. All rights reserved.
Key words: Chronic severe hepatitis B; Multiple organ
dysfunction; Human growth hormone; Insulin-like growth
factor-1; Lactulose
Ding HG, Shan J, Zhang B, Ma HB, Zhou L, Jin R, Tan YF, He
LX. Combined human growth hormone and lactulose for
prevention and treatment of multiple organ dysfunction in
patients with severe chronic hepatitis B. World J Gastroenterol
2005; 11(19): 2981-2983
https://www.wjgnet.com/1007-9327/11/2981.asp
INTRODUCTION
Severe viral hepatitis, namely severe acute or chronic liver
failure, develops quickly with an extremely dangerous
prognosis. Its mortality rate is between 60% and 90%[1] and
there is still no breakthrough in medical treatment. It has
been proved that multiple organ dysfunction is the main
cause of death of these patients[2,3]. Therefore, it is very
important to treat effectively severe hepatitis patients with
multiple organ dysfunction. The mortality would fall significantly
if patients with multiple organ dysfunction are properly
treated. The aim of our study was to evaluate the efficacy
and safety of recombinant human growth hormone (rhGH)
in combination with lactulose for treatment and/or
prevention of chronic severe hepatitis B with multiple organ
dysfunction. The mechanism of these drugs was also studied.
MATERIALS AND METHODS
Patients and controls
Forty-eight patients with chronic severe hepatitis B from
January 1999 to February 2002 were enrolled. Chronic
severe hepatitis was previously defined during the National
Conference of Xi’an in 2002. In brief, inclusion criteria
were as follows: a history of chronic hepatitis or liver
cirrhosis; severe asthenia, serum total bilirubin more than
171 μmol/L; prothrombin time activity (PTA) less than
40%. Of those patients, 28 were in treatment group (23
males and 5 females, average age of 42.6 years), 20 were in
control group (17 males and 3 females, average age of
41.5 years). Their clinical data, such as liver and kidney
biochemical parameters, were comparable.
Protocol of study
Treatment methods All patients in treatment group received
standard treatment: rhGH 4-4.5 IU im injection once daily
2982 ISSN 1007-9327 CN 14-1219/ R World J Gastroenterol May 21, 2005 Volume 11 Number 19
for 2-4 wk, enema containing 0.9% normal saline 100 mL
plus lactulose 30 mL and metronidazole 2.0 g once every 2
d for 2-4 wk. Patients in control group only received standard
treatment.
Sample collection Venous blood 3 mL was collected at
6:00-7:00 a.m., and centrifuged at 4 , stored at -20 .
Clinical symptoms and complications were recorded and
the patients were followed-up for at least 6 mo according
to CRF.
Biochemical tests Serum growth hormone (GH), insulinlike
growth factor-1 (IGF-1), insulin-like growth factor
binding proteins 1, 3 (IGFBP1, IGFBP3) were respectively
measured by ELISA. All the test kits were purchased from
DSL Corporation, and used according to their manufacturer’s
instructions.
Efficacy endpoints Clinical symptoms were completely
improved and complications were controlled in 4 wk, and
no new complications occurred. Liver functions were
markedly improved in 3 mo, the total bilirubin decreased
by 30-60%. PTA value was increased. All patients were
followed-up for 6 mo.
Statistical analysis
Statistical evaluations were performed using SPSS 10.0
statistical software. Clinical effects of the two groups were
compared by χ2 test, quantitative data were expressed as
mean±SD and analyzed with two-way variance test. P less
than 0.05 was considered statistically significant.
RESULTS
The results of this study indicated that the clinical symptoms
of 90% of the patients were markedly improved. The total
effective rate was 75% in treatment group and 40% in
control group. There was a significant difference between
the two groups (P<0.05).
In treatment group, serum prealbumin, cholesterol and
total protein in 60% of the patients were significantly
increased (P<0.05, Table 1). The albumin level could
maintain for 2-4 wk after rhGH was stopped. In contrast,
prealbumin, cholesterol and albumin in 60% of the patients
in control group were consistently decreased.
The level of serum GH in chronic severe hepatitis
patients was relatively higher than that in normal subjects.
But it decreased after rhGH was used for 2-4 wk. The level
of IGF-1 and IGFBP3 had a trend increase, but there was
no statistical difference. The serum IGFBP1 level was
markedly increased (Table 2). The mortality rate of the patients
with high serum GH level after treatment was nearly 100%.
DISCUSSION
Up to now, there has been no ideal treatment for severe
hepatitis. It was reported that the mortality rate of severe
hepatitis was more than 80% if liver transplantation was
not performed[4]. Liver transplantation is the optimal choice
for treatment of liver failure. Therefore, the fundamental
purpose of internal medical treatment is to make the state
of illness stable and to wait for appropriate liver donor for
liver transplantation[4]. Many complications in severe hepatitis
patients had a close relation to the prognosis[1,2]. It was found
in our previous study that the mortality rate of severe
hepatitis patients with more than two complications was
72.8% and nearly 100% of those with more than four
complications. The pathophysiological mechanism of
multiple organ dysfunction in severe hepatitis patients is
still not clear[1,3]. At present, it is considered that infection
and severe endotoxemia could play an important role
in severe hepatitis with multiple organ dysfunction[1-3].
Malnutrition of severe hepatitis patients, especially chronic
severe hepatitis patients, was the leading cause of accompanying
infections[1,5]. Therefore, if infection is controlled effectively
and endotoxin is removed, malnutrition may improve, and
the multiple organ dysfunction of severe hepatitis patients
may be prevented and cured effectively. According to this
hypothesis, we designed a new therapy method for chronic
severe hepatitis: human GH combined with lactulose enema.
GH, composed of 191 amino acids, is a sort of single
chain polypeptide secreted by adenohypophyseal acidophils.
It is well known that GH not only promote growth and
development but also has comprehensive biological functions,
concerning cell multiplication and differentiation. GH could
also regulate immunity and metabolism[6]. Furthermore, liver
is the main target organ of GH in vivo, and the center of
GH-IGF axis[7,8]. It has been found that decreased serum
IGF-1, IGFBP3 and ALS had a close relation to liver reserve
function and the prognoses of liver cirrhosis patients[9]. It
was also found[10] that serum IGF-1 and IGFBP3 were
decreased in severe viral hepatitis patients while IGFBP1
was increased. The decrease of IGF-1 also had a close
relation to the prognosis of severe hepatitis patients. Assy
et al.[9], performed hypodermic injection in liver cirrhosis
patients with rhGH 0.4 U/kg, and measured serum IGF-1
24 h later with RIA. If IGF-1 <10 nmol/L, the prognosis
was bad, the 1-year survival rate was only 15%; if IGF-1
Table 1 Effects of rhGH on liver function of patients with severe
chronic hepatitis B (mean±SD)
Marker of liver function Pretreatment 2-wk treatment 4-wk treatment
n = 28 n = 28 n = 16
Total protein (g/L) 51.6±4.3 67.8±8.4a 69.2±7.8
Prealbumin (g/L) 80±28 107±54a 108±55
Albumin (g/L) 26.1±4.1 30.2±5.3a 31.9±5.1b
Cholesterol (mg/dL) 76±17 86±32a 96±39
Total bilirubin (mg/dL) 15±14 20±16 12±13
PTA (%) 21.3±5.5 24.7±12.2 36.8±7.9
ALT (IU/L) 117±210 83±77 59±43
AST (IU/L) 171±243 104±79 76±56
aP<0.05, bP<0.01 vs pretreatment.
Table 2 Effects of rhGH on GH-IGF axis in patients with severe
chronic hepatitis B (mean±SD)
Marker of GH-IGF axis Pretreatment (n = 15) 2-wk treatment (n = 15)
GH (ng/mL) 10.4±7.6 6.2±8.1a
IGF-1 (μg/mL) 6.3±4.5 8.8±6.7
IGFBP1 (ng/mL) 56.8±47.2 89.7±50.3a
IGFBP3 (μg/mL) 3.5±1.7 5.1±3.4
aP<0.05 vs pretreatment.
Ding HG et al. Human growth hormone and lactulose on multiple organ dysfunction 2983
>10 nmol/L, the 1- and 2-year survival rates of liver
cirrhosis patients were both 100%; indicating that IGF-1
could be used to forecast the prognosis of liver cirrhosis
patients[11,12]. Our study showed that the GH level of chronic
severe hepatitis patients was high, extraneous human GH
could increase IGFBP1, IGF-1 and IGFBP3, while serum
GH level was decreased. These results indicated that
extraneous GH might improve GH resistance state of chronic
severe hepatitis[10-12]. GH resistance is related to metabolic
disturbances, such as malnutrition, energy metabolism
abnormity, both of which play an important part in
secondary hepatocyte damage and multiple organ dysfunction
of severe hepatitis. On the other hand, the prognoses of
severe hepatitis patients depend on the balance between
necrosis and regeneration of liver. Many cell factors (such
as HGF, HSGF) can stimulate the proliferation of hepatic
cells, but the clinical curative effect is not satisfactory. It
has been found that epidermal growth factor could
significantly alleviate the multiple organ failure due to
thioacetamide. Our study also showed that the use of human
GH for 2-4 wk in treating chronic severe hepatitis patients
could reduce the occurrence and development of
complications, prolong the survival and improve the lifequality
of patients. Serum prealbumin, albumin level
increased and the overall effective rate was 75% without
any obvious side effect[13].
It has been proved that toxic substances (such as
endotoxin, NH3, γ-GABA, etc.) and high level of inflammatory
cell factors in the serum of severe hepatitis patients could
lead to fever, hypotension, ARDS, and eventually multiple
organ dysfunction[1]. Besides, these substances may affect
the regeneration capacity of liver. Therefore, it is important
to look for an effective method to reduce endotoxin and
inflammatory cell factors. Biological and non-biological
artificial livers could be used to treat severe hepatitis, through
reducing the toxic substances in serum, such as endotoxin
and bilirubin. However, most of the toxic substances could
combine with proteins into large molecules and could not
be filtered through, so treatment should be conducted
repeatedly. Some useful cell factors were also filtered.
Meanwhile there were some complications, such as
secondary bacterial or virus infections. For this reason, the
long-term treatment of severe hepatitis with artificial liver
should be further explored, and at present it has been only used
as the transient therapy before liver transplantation[3].
Professor Fan (Hong Kong University) et al., used selective
filtration to remove toxic substances, and retained some
liver growth factors meanwhile. They achieved perfect
results in animal experiments, but there has been no clinical
experiment[3]. Some scholars utilized tumor necrosis factor
antibody to treat experimental hepatic failure animals, and
also obtained good results, but there is no clinical experiment
report, either.
Lactulose can be decomposed into lactic acid and acetic
acid by enteric bacteria. Both of them can acidify the
intestinal tract, and restrain the production and absorption
of toxic substances, such as endotoxin, NH3, etc., so that
they can remove endotoxin perfectly without severe side
effects. It has been proved by clinical researches that
lactulose can remove endotoxin and decrease the generation
of endotoxin. In this study, we preliminarily observed the
curative effects of human GH associated with lactulose in
treating chronic severe hepatitis, and achieved satisfactory
results. In treatment group, the clinical symptoms of most
of the patients were improved evidently. According to the
modified criteria of therapeutical effect, the markedly
effective rate was 21.4% (6/28), the effective rate was 53.5%
(15/28), the overall effective rate was 75%, and there was
a significant difference compared to the control group. This
result indicated that human GH combined with lactulose could
effectively prevent exacerbation of severe hepatitis, and prevent
and cure its complications. Its mechanisms may lie in the
following factors: preventing the generation and absorption of
intestinal endotoxin, curing endotoxemia; improving GH
resistance of chronic severe hepatitis patients and abnormal
metabolic status, and increasing serum prealbumin, albumin
and cholesterol level. It is preliminarily concluded that
human GH combined with lactulose could prevent and cure
severe hepatitis complicated by multiple organ dysfunction.
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