Clinical use of growth hormone and glutamine in short bowel syndrome

Uso clínico de hormônio de crescimento e glutamina em síndrome do intestino curto

CLINICAL USE OF GROWTH HORMONE AND GLUTAMINE IN SHORT BOWEL SYNDROME

Celso Cukier, Dan L. Waitzberg, Viviane Chaer Borges, Maria de Lourdes T. Silva, Joaquim Gama-Rodrigues and Henrique Walter Pinotti

RHCFAP/2957

CUKIER, C. et al. . - Clinical use of growth hormone and glutamine in short bowel syndrome. Rev. Hosp. Clín. Fac. Med. S. Paulo 54(1) 29 - 34, 1999.

SUMMARY: Growth hormone (GH) and glutamine (GLN) are considered bowel trophic factors and are used experimentally after bowel resection. Their clinical uses in short bowel syndrome (SBS) are still not standardized. It is of interest to verify metabolic, nutritional and side effects of the association of GH and GLN in SBS. Three patients, 39 (A), 33 (B), and 01 years old (C) underwent bowel resection with jejunum anastomosis 15 cm (A) and 60 cm (B) distant from the Treitz angle, and 40 cm (C) preserving the ileo cecal valve. GH Saizen (Serono - A), Genotropin (Pharmacia - B), and Norditropin (Novonordisk C) were administered in doses of 0.14 mg /kg/day. GLN (0.4 g/kg/day) was given orally for 10 days (A), 30 days (B) and 60 days to patient C (0.28 g/kg/day). Central TPN and adequate oral diet was administered according to the bowel adaptation phase. On the first day after beginning treatment patient A exhibited symptoms of hypoglycemia. There were no other side effects. After treatment, body weight was higher and analysis by bioelectrical impedance showed more lean mass and less fat mass compared to pre-treatment measurements. Nitrogen retention was progressively higher with treatment. Simultaneous treatment with GH and GLN does not cause significant side effects, and is associated with a favorable distribution of the body compartments and nitrogen retention in patients with the short bowel syndrome.

DESCRIPTORS: Growth hormone. Glutamine. Short bowel syndrome. Clinical use.

In the last decades, progress in the surgical and anesthetic procedures and postoperative resuscitation has resulted in higher immediate survival rates of patients undergoing extensive short bowel resections. ^{4, 15, 31, 46, 47}

After the initial postoperative phase, nutritional maintenance of these patients becomes a concern because of the metabolic consequences of the short bowel syndrome (SBS), primarily malabsorption due to the small extension of the remaining bowel.⁵⁹

Several factors influence the absorption of nutrients, including extension and site of the resected bowel; presence or absence of the ileo-cecal junction; bowel function; remaining colon, stomach, liver, and pancreas; adaptation changes of the gastrointestinal tract; and primary intestinal disease. ^{2, 13, 14, 15, 49}

Total parenteral nutrition (TPN) has added years to the lives of patients with SBS. However, after six to eight years of total parenteral nutrition, metabolic disorders appear, causing increased mortality rates in these patients.^{16, 18}

Therefore, there is increased interest in researching the possibilities of pharmacologically increasing intestinal absorption, either by offering specific nutrients or by increasing the absorption area of specific nutrients. ^{5, 6, 7, 10, 22, 26}

Among the trophic factors that could act on the bowel, glutamine (GLN) and growth hormone (GH) are indicated. GLN is an amino acid that becomes conditionally essential in catabolic states.³² The role of GLN in healing after severe trauma was described in 1979, by FURST 19. GLN is the main oxidation source of epithelial cells, 8 and is used as energy source for cellular division of enterocytes, colonocytes, and lymphocytes. ^{17, 30, 40, 41} It is possible that GLN regulates protein degradation.⁴⁸ One of the most important functions of GLN is the transfer of nitrogen to the tissues.^{40, 43} Glutamine is the most important substrate for the renal synthesis of ammonia ⁵⁰, is involved in the regulation of the glycogen hepatic synthesis, ³⁰ and influences nucleotide and protein synthesis. ⁵³

Growth hormone (GH) is a small protein that contains 191 amino acids in single chain that has a molecular weight of 22.005 daltons, and is produced by the anterior hypophysis over the entire lifespan.²⁰

GH receptors in human beings are present in the liver, adipocytes, fibroblasts, lymphocytes, and cells of the bowel tract, especially in enterocytes and colonocytes. The effector mechanisms of the receptor are not completely known³⁴. In the liver, they are involved in intra-cellular transport of amino acids; synthesis of mRNA; enzymatic activation of ribosomes for protein synthesis; lipoprotein-lipase activation; and stimulation of hematopoietic cell mitosis, ornitine-descarboxylase, and polyamine increase.³⁴

GH decreases protein catabolism, reducing amino acid oxidation. It favors the nitrogen balance, even on hypocaloric nutritional support²², reducing glucose oxidation and increasing fatty acid oxidation up to three times. GH increases IGF-1 levels in 25%, insulinemia in 50%, and provokes few increases in glycemia. A beneficial effect is observed in the distribution of body fluids. It preserves cellular mass, maintains the intracellular water compartment, and avoids extracellular liquid retention¹⁰.

GH has a positive effect on immunity. It stimulates nonspecific defense mechanisms mediated by leukocytes, increases immunoglobulin production, stimulates suppressor T lymphocytes, and increases the CD4/CD3 ratio by 85%. These effects are not observed in patients with acquired immunodeficiency syndrome or undergoing organ transplants.³⁸

The use of GH in TPN patients has been proven beneficial in critical situations such as surgeries, trauma, infections, and chronic diseases. It is associated with nitrogen retention, protein synthesis, faster recovery, less hospital time, and better quality of life. ^{6, 22, 28, 35, 45, 58, 60} The postoperative use of GH attenuated skeletal muscle GLN loss ^{22, 28} and protein muscle loss after surgery. ²³

In preliminary observations in SBS patients, the combined use of GH and GLN promoted body weight gain and nutritional status improvement by increasing absorption of nitrogen, calories, sodium, and water. ^{6, 7}

Isolated use of GLN and GH provokes trophic effects on the small intestine under several clinical conditions, and it is possible that GLN and GH have synergic effects on the function and structure of the small intestine, promoting adaptation after massive resection.

In the current study, three cases of bowel resection are presented in which a large part of the absorption capacity of the small intestine was lost. The use of GH and diet enriched with GLN for a short period improved conservation of body compartments and nitrogen retention.

CASE REPORTS

Case 1 - Patient MPS, female, 39 years old, Caucasian, born in São Paulo. In January 1995, she had acute abdominal pain diagnosed as mesenteric thrombosis. She underwent an extensive jejunal and ileo-cecal valve resection. The remaining jejunum measured 15 cm from the Treitz angle, and it was anastomosed to the ascending colon (^{picture 1}).

Immediately after surgery the patient was instructed to begin oral feeding without restrictions. After 3 months, patient entered the Multidisciplinary Short Bowel Syndrome Ambulatory (AMULSIC) of the Stomach, Duodenum and Small Intestine Group of Gastrointestinal System Surgery Chain of the Hospital das Clinicas of University of São Paulo Medical School. Nutritional evaluation (Table 1) indicated serious malnutrition and inadequate food ingestion with reduced absorption. The patient was admitted and treated with TPN (2000 non-protein kcal/day and 12.8 g/day of nitrogen). Oral diet followed the intestinal adaptation phases.

After 3 weeks of TPN, the patient was in metabolic and hydroelectrolytic balance. For 10 days, 0.14 mg/kg/day of subcutaneous (SC) GH, (Saizen®, Serono Laboratory of Brazil) was given, always at the same time of day. Glutamine (Ajinomoto LTDA) was offered orally in a 0.4 g/kg/day dose.

Clinical symptoms compatible with hypoglycemia (80 mg/dl) were found in the first day after beginning treatment with GH. There were no other side effects during the treatment period.

On day 10 after the introduction of GH, increased body weight by 2.7% was observed compared with pre-treatment measurements. Increased lean mass (9.3%) and reduction of the fat compartment (-1.7%) were identified by electric bioimpedance, in comparison to the beginning of treatment.

Daily nitrogen balance was determined by total urinary nitrogen (N) dosage less total ingestion of N. Fecal N was assessed as 7 g/day. Nitrogen retention was progressively higher with each successive week. (Table 2).

IGF-1 dosage was high in the sixth day after beginning treatment with GH and GLN. In the sixth day after the end of treatment its level returned to the former value (Table 3).

Case 2 - Patient NRP, male, 33 years old, Caucasian, born in São Paulo. In May of 1995, he had acute mesenteric thrombosis and underwent an extensive enterectomy that left 60 cm of jejunum anastomosed to the ascending colon.

After surgery, the patient was fed an oral diet that progressed to a general diet without restrictions. After four months he was admitted in intensive care unit because of serious hypokalemia. At this time he had a 40% weight loss in relation to his usual weight, a high number of evacuations (8-10/day,) and persistent hypokalemia. Central vein TPN (2.400 non-protein kcal and 22 grams of nitrogen per day) was begun. Oral diet appropriate to this phase of intestinal adaptation was administered. Initial nutritional evaluation can be seen in the table 1.

After metabolic and hydroelectrolytic balance was achieved, 0.14 mg/kg/day of subcutaneous GH (Saizen ® - Serono laboratory of Brazil) and 0.4 g/kg/day of GLN (Aji-no-moto) . were administered.

After treatment, the patient's body weight increased 4.9%. Bioelectric impedance showed an increase in lean mass and reduction of the fat compartment in comparison to pre-treatment measurements. (Table 1).

Nitrogen balance (Table 2) was determined from the total urinary nitrogen dosage (micro-Kjeldahl method) subtracted from the oral ingestion and total supply of nitrogen. Fecal N was assessed as 7 g/day. With the use of GH, there was a more pronounced nitrogen retention in the first ten days (Table 2).

Plasma IGF-1 levels were higher on the sixth day after beginning treatment (220 ng/mL vs. 440 ng/mL), and returned to a normal level on the fourth week of treatment (Table 3).

Case 3 - Patient P.P., male, 1 year old, Caucasian, born in Limeira, São Paulo. Since birth he had difficulty ingesting food and developed vomiting episodes that became sporadic with growth. In November 1996, after clinical symptoms of vomiting and abdominal distention, he underwent an exploratory laparotomy with an extensive enterectomy for volvulus. He was left with 40 cm of small intestine. The ileo-cecal valve and the colon were preserved in their integrity.

A central vein catheter was inserted, and feeding by oral and parenteral routes was begun. For the subsequent period of 60 days, he received 0.14 mg/kg/day of subcutaneous GH (Norditropin® - Novonordisk) and 0.28 g/kg/day of oral GLN (Aji-no-moto).

The patient's body weight increased by 6.9%. Bioelectric imped ance measurements revealed a lean mass increase (9.7%) and reduction of the fat compartment (13.6%) compared to pre-treatment measurements (Table 1).

Nitrogen balance was determined from the difference of the total urinary nitrogen (micro-Kjeldahl method) subtracted from the oral ingestion. The fecal nitrogen loss was assessed as 7 g/day (Table 2).

Plasma IGF-1 levels were elevated above pre-treatment levels during the entire GH treatment period (Table 3).

DISCUSSION

These case studies describe the nutritional changes in three patients with severe short bowel syndrome who had been treated for a short period with GH and GLN in association to TPN. Three patients presented favorable modifications in their body composition and in nitrogen retention.

Because of the deficient absorption area in short bowel syndrome, mal-absorption, diarrhea, and loss of bases and potassium occurs, accompanied by mobilization of fat deposits and muscle proteins to assist the protein-caloric requirements not supplied by food ingestion. These clinical signs can culminate in metabolic and hydroelectrolytic unbalance and the development of malnutrition.¹³

The conventional nutritional treatment for short bowel syndrome patients is the use of TPN. However, complications arising from long-term intravenous feeding resulting from decreased the bowel trophism and consequently favoring bacterial translocation. ²⁵ In mice, atrophy of the small intestine mucosa associated with TPN infusion without GLN is reduced when intravenous GLN is added. ^{24, 41} In several experimental models, it was possible to observe the beneficial effect of GLN on small intestine by the increase of jejunal villus and of DNA content of the mucosa of mice that underwent chemotherapy and abdominal radiotherapy 8 or bowel resection. ^{54, 57}

The use of GLN in short bowel syndrome is justified, since GLN is the preferred energy source for rapidly proliferating cells such as enterocytes and white cells of the blood. ^{17, 40} GLN participates in the metabolic nitrogen cycles. There is an inter-organic flow of GLN between liver, small intestine, kidney, and muscle. ^{36, 41, 56}

GLN plays a role in protein synthesis as well as influencing bicarbonate production by the kidney, being the most important substrate for renal amniogenesis.⁴⁴ GLN increases the rate of protein turnover in the muscle61 and increases plasma concentrations of the arginine and glutamate, stimulating GH secretion1.

At basal metabolic state, the small intestine cells use GLN as an energy source. In critical and hypercatabolic states the consumption of GLN increases. Simultaneously, the liver uses GLN in the gluconeogenesis for glucose synthesis. After severe organic injury, plasma levels of GLN decrease 36, partly because the small intestine uses it faster than it is released by skeletal muscle. ^{24, 25, 37}

The use of GLN in conditions of extensive bowel resection improved body weight gain and increased the size and absorption capacity of the remaining bowel. ^{3, 66}

In the present study recombinant GH, obtained by genetic engineering, were subcutaneously used in doses of 0.14 mg/kg/day, following a standardized schedule. ^{12, 66} It was observed, in case 1 that on the second day of GH application, there were hypoglycemia symptoms that reverted with the administration of intravenous glucose. Other side effects related to GH therapy, such as hypothyroidism, edema, and pain in the injection site were not observed.

In human beings, body weight changes were noticed in several clinical situations involving GH therapy, such as increased weight in trauma patients 55 and weight maintenance in gastric and colon resections. ⁶⁴ Increase of body mass was associated with reduction of fat synthesis and increased bone density in the spine. ⁵¹

The use of GH reduced nitrogen loss and stimulated nitrogen retention in patients under different catabolic conditions in the intensive care unit, ^{27, 32} such as burns ,⁶³ sepsis, ^{43, 64} trauma 45, gastric and colon resections 22 and short bowel syndrome. ^{7, 11, 39, 62}

The actions of GH affect the body composition, resulting in a gradual gain of body weight, increased lean body mass, and stimulation of total body fat mobilization.²⁷ The reduction of total nitrogen loss can be explained by the increased protein synthesis stimulated by GH. The muscle ribosome content is maintained and promotes nitrogen retention even with a hypocaloric diet. ^{34, 35}

The association of GH with a diet enriched with GLN facilitated the small intestine growth after extensive intestine resection in rat (Murad et al., 1996). Those observations are supported by the findings of SCHULMAN et al. ³², who noted an increase of the mucosa surface on the small intestine in Sprague-dawley mice with 75 to 80% bowel resection under GH treatment. BENHAMOU et al. 5 verified that mice undergoing an 80% bowel resection that received GH experienced an increase of 20% on the remaining bowel. A controlled experimental study evaluated the proliferative effects of GH in Wistar rats undergoing 95% of bowel resection. An increased proliferation of the bowel mucosa was demonstrated by an immunohistochemical method. ³⁹

GH also has effects on the colon mass and its biomechanical force 9, which could extend the time of intestinal progression 28, a beneficial effect in patients undergoing an extensive bowel resection.

In the current study the combined use of TPN, GH, and GLN increased body weight and nitrogen retention in all patients. These effects can be considered beneficial after massive bowel resection in which it is difficult to promote nitrogen retention.

The observed results and the absence of significant side effects support the supposition that the combined use of GH and GLN in association with TPN favors bowel adaptation and facilitates the nutritional recovery of patients undergoing massive bowel resection. However, further controlled prospective studies are required to verify the endurance of the obtained effects and to test the effect of prolonged combined therapy with GH and GLN in studies.

RESUMO

RHCFAP/2957

CUKIER, C. e col. - Uso clínico de hormônio de crescimento e glutamina em síndrome do intestino curto. Rev. Hosp. Clín. Fac. Med. S. Paulo 54(1): 29 - 34, 1999.

Hormônio de crescimento (GH) e glutamina (GLN) são fatores tróficos da mucosa intestinal, utilizados experimentalmente pós ressecção intestinal maciça. O uso clinico de GH e GLN em síndrome do intestino curto (SIC) ainda não está padronizado. Torna-se de interesse verificar os efeitos metabólicos, nutricionais e colaterais da associação do GH e GLN em SIC grave de origem recente. Três pacientes, com idades de 39 anos (A), 33 anos (B) e 1 ano (C) foram submetidos à enterectomia com anastomose do jejuno a 15 cm (A) e 60 cm (B) do angulo de Treitz com o cólon ascendente e a 40 cm ( C) do ângulo de Treitz, preservando-se a válvula íleo-cecal. Administrou-se GH (Saizen - Serono (A); Genotropin - Pharmacia (B); Norditropin - Novonordisk ( C)) na dose de 0,14 mg/Kg/dia SC e glutamina VO (Ajinomoto) nas doses de 0,4 g/kg/dia (A - 10 dias e B - 30 dias) e 0,28 g/kg/dia ( C ) por 60 dias consecutivos. Ministrou-se NPT central e dieta oral adequada `a fase de adaptação intestinal. Ocorreu quadro clínico compatível hipoglicemia no caso A (80 mg/dl) no primeiro dia após inicio do tratamento. Não ocorreram outros efeitos colaterais. Em relação ao pré-tratamento observou-se aumento do peso corpóreo, aumento de massa magra e redução do compartimento gorduroso medidos por bioimpedância elétrica. Balanço nitrogenado diário foi obtido pela dosagem de N total urinário subtraída da ingestão total de N. A retenção nitrogenada foi progressivamente maior. A associação de GH e GLN não proporciona efeitos colaterais, melhora a distribuição do compartimento corporal e retenção de nitrogênio em síndrome do intestino curto.

DESCRITORES: Hormônio do crescimento. Glutamina. Síndrome do intestino curto. Uso clínico.

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Received for publication on the 06/07/98

Study conducted at the Discipline of Stomach, Duodenum and Small Intestine of Digestive System Chain of the "Hospital das Clínicas" of University of São Paulo Medical School and Group of Parenteral and Enteral Nutrition of "Hospital São Joaquim" (GANEP), São Paulo.

Publication Dates

• Publication in this collection
  12 Sept 2000
• Date of issue
  Feb 1999

History

• Received
  06 July 1998