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Nutrition in Clinical Practice
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Invited Reviews

Criteria for the Use of Recombinant Human Growth Hormone in Short Bowel Syndrome

Neha R. Parekh, MS, RD, LD, CNSD*,{ddagger} and Ezra Steiger, MD, FACS, CNSP*,{dagger},{ddagger}

* Intestinal Rehabilitation Program,{dagger} Nutrition Support and Vascular Access Department, and {ddagger} Department of General Surgery, Cleveland Clinic Foundation, Cleveland, Ohio

Correspondence: Neha R. Parekh, MS, RD, LD, CNSD, Intestinal Rehabilitation Program, Cleveland Clinic Foundation, 9500 Euclid Avenue, A80, Cleveland, OH 44195. Electronic mail may be sent to parekhn{at}ccf.org.

Extensive resection of the intestinal tract with resulting malabsorption is known as short bowel syndrome (SBS). Adaptation and rehabilitation of the remaining small bowel occurs spontaneously after resection and can be enhanced by diet, medications, and use of intestinal trophic factors such as recombinant human growth hormone (r-hGH). Many trials have been published on the influence of r-hGH therapy in SBS patients, with varying results. Analysis of the trials has produced a set of criteria that can be used to define the patient most likely to benefit from r-hGH therapy.

Short bowel syndrome (SBS) is a disorder caused by an extensive resection of the intestinal tract, resulting in diarrhea, malabsorption, malnutrition, nutrient deficiencies, and fluid and electrolyte abnormalities. Spontaneous adaptation of the remaining bowel to compensate for the loss of intestinal length occurs shortly after resection and generally continues for up to 2 years.1–3 Parenteral nutrition (PN) is often needed while the adaptive process occurs and may be required indefinitely, depending on the extent of recovery of bowel function. Unfortunately, PN is not without substantial risks and drawbacks, including catheter-related infections, venous thrombosis, hepatobiliary dysfunction, metabolic bone disease, elevated costs, and a reduced quality of life. In addition, the absence of luminal nutrients associated with the prolonged use of PN can lead to atrophy and increased permeability of the remaining small bowel.4

Measures taken to enhance or accelerate intestinal adaptation with the goal of reducing or eliminating dependence on PN in SBS patients are collectively recognized as intestinal rehabilitation. Several rehabilitation strategies, including specialized diet, antidiarrheal and antisecretory agents, and intestinal trophic factors such as growth hormone and glutamine have been described in the literature, with variable results.5 In 2004, the US Food and Drug Administration approved the use of recombinant human growth hormone (r-hGH) as an adjunctive pharmacologic therapy for the treatment of SBS-induced malabsorption and malnutrition. Mechanisms of action, clinical trials, and strategies for the use of r-hGH are summarized here, with emphasis on the selection and care of patients most likely to respond to this novel therapy.


   Growth Hormone and Intestinal Adaptation
Top
 Growth Hormone and Intestinal...
Patient Selection
 Parameters for Weaning PN
 Future Directions
 
Human growth hormone is produced in the anterior pituitary gland and secreted into the blood-stream in response to luminal nutrients. Growth hormone plays a role in the enhancement of several processes of human growth and metabolism (Table 1). Anabolic properties of growth hormone include the stimulation of protein synthesis, amino acid transport, and insulin-like growth factor-1 (IGF-1) production.6 IGF-1 is an important mediator of the effects of growth hormone on intestinal adaptation and regeneration after extensive resection.7 The exogenous administration of human growth hormone has been shown to enhance intestinal mucosal hyperplasia, increase colonic mass and mucosal adaptive surface area, and augment biomechanical strength in human and animal models of SBS.8–10 Functional improvements have also been documented after r-hGH therapy, including enhanced nutrient transport across the small bowel mucosa and improved fluid and electrolyte absorption from the remnant small bowel.11–13


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  		Table 1 Effects of r-hGH on human metabolism and growth6,8-13

 

Clinical trials investigating combinations of diet, glutamine, and r-hGH have subsequently been performed in human SBS patients. Two uncontrolled trials and 1 case series collectively including >120 PN-dependent SBS patients found that 40% of patients were free of PN at up to 1 year after bowel rehabilitation therapy with r-hGH, glutamine and a modified diet.14–16 A recent prospective, randomized, double-blind, placebo-controlled trial by the same group found that PN-dependent SBS patients receiving r-hGH and an optimal diet with or without glutamine had significantly greater reductions in PN than patients receiving glutamine and diet alone (p < .001).17

Results of trials examining the influence of r-hGH on direct measures of intestinal nutrient and fluid absorption have been less conclusive.18–24 Byrne et al18 found a significant increase in protein (p ≤ .006), carbohydrate (p ≤ .02), water (p ≤ .002), and sodium (p ≤ .04) absorption after 3 weeks of treatment with r-hGH, glutamine, and a modified diet. Nutrient balance and net absorption were calculated from daily measured enteral intake and stool losses. Scolapio et al19 measured nutrient and fluid absorption using both clinical and biochemical parameters. This group found a significant increase in sodium (p = .03) and potassium (p = .007) absorption but no notable change in macronutrient or fluid absorption after 3 weeks of r-hGH, glutamine, and diet therapy.

Conflicting outcomes among trials of r-hGH in SBS may be attributed to the numerous differences in study protocols. This includes variations in application of diet intervention, use of glutamine, dose of growth hormone, presence of colon, length of remaining small bowel, use of PN, total daily caloric intake, degree of malnutrition, presence of mucosal disease, and study setting. Most of the reports did, however, agree on 2 points: (1) any improvements seen in body weight, lean body mass, or percent body fat returned to baseline soon after discontinuing r-hGH therapy, and (2) appropriate patient selection for r-hGH therapy is highly important.


   Patient Selection
Top
 Growth Hormone and Intestinal...
 Patient Selection
Parameters for Weaning PN
 Future Directions
 
There are several factors to consider when selecting patients for r-hGH treatment (Table 2). Growth hormone therapy is expensive (about $20,000 for a 4-week supply), and its use in varying dosages has been associated with side effects such as peripheral edema, glucose intolerance, arthralgias, and injection-site reactions. However, a decreased risk of PN-related complications, an increased quality of life, and a substantial cost savings (1 year of PN is about $100,000, resulting in a savings of $80,000 per year) are all benefits of reduction in PN use that support the effort to find the appropriate patient for r-hGH therapy.


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  		Table 2 Patient selection for r-hGH therapy17,24,26

 

Remaining Bowel Length
Preservation of the colon after small bowel resection may have a large impact on the outcome of a bowel rehabilitation program with or without the use of r-hGH therapy. Advantages of an intact colon include prolonged intestinal transit time and carbohydrate salvage through bacterial fermentation, both of which contribute to improved nutrient, fluid, and electrolyte absorption. Trials examining the effects of treatment with r-hGH in SBS show that PN is more likely to be weaned in patients with remnant colon than in those without a colon.14–16,18,23–26

Wilmore et al15 investigated the minimum amount of jejunum-ileum anastomosed to a portion of colon required for patients to be free of PN after bowel rehabilitation with r-hGH therapy. They found that patients with a small intestinal length to body weight ratio of ≥0.5 cm/kg (equating to 25 cm for a 50-kg person) could be weaned completely from PN. However, a subsequent study from the same group revealed that patients with as little as 12 cm of jejunum-ileum with an intact colon have the potential to be independent of PN.16

Benefit has not been demonstrated with r-hGH, glutamine, and specialized diet in patients with 50 cm or less of small bowel and no remaining colon.14,16,17,27 Patients with >50 and <100 cm of small bowel and no colon will likely remain PN-dependent but have the potential for reduction of weekly PN requirements after r-hGH, glutamine, and diet therapy.17 Treatment with r-hGH therefore should be limited to patients with at least 50–200 cm small bowel without a colon or ≥15 cm jejunum-ileum with ≥30% functioning colon or ≥90 cm jejunum-ileum with <30% functioning colon.14,17

Residual Bowel Disease and Underlying Disease States
The presence of active disease, such as Crohn's disease, enterocutaneous fistulas, or radiation enteritis, in the residual small bowel has an inhibitory effect on intestinal adaptation.28 Intensive bowel rehabilitation efforts with antidiarrheal agents and dietary fiber may lead to complete obstruction in patients with a partial obstruction due to strictures or adhesive disease. If active Crohn's disease is suspected, the patient should undergo clinical evaluation and appropriate medical or surgical treatment before initiating r-hGH therapy.

Patients with SBS and impending liver failure should be evaluated for further therapy, including surgical options such as transplantation, before initiation of r-hGH treatment (Steiger et al, unpublished data). Active neoplasia is a contraindication to r-hGH therapy, and recurrence during the past 10 years should be ruled out in potential r-hGH treatment candidates with a history of cancer. Patients with acute critical illness, sepsis, or inflammation, including catheter-related infection within the past 3 months, are not considered to be in stable clinical condition and should not receive r-hGH therapy. Cases of new-onset impaired glucose intolerance have been associated with r-hGH treatment; thus, r-hGH should be used with caution in SBS patients with preexisting diabetes mellitus.29

Timing of Administration Postresection
Debate exists over the optimal time at which r-hGH should be initiated post–intestinal resection. Zhu et al30 published an uncontrolled, prospective case series demonstrating positive outcomes after bowel rehabilitation therapy including r-hGH administration within 3–6 months of extensive small bowel resection. Other successful trials have waited more than 1 year and up to 12 years postresection to begin r-hGH therapy.17,18,24 Experts advise delaying the use of r-hGH therapy until after the process of spontaneous adaptation has begun, after the patient is well nourished, and after other standard rehabilitation modalities have been given time to influence the adaptive process (Steiger et al, unpublished data; DiBaise et al, unpublished data).2,3

Investigators have also been unable to ascertain the most effective dose (0.024–0.14 mg/kg/day), or duration of administration (3–8 weeks) of r-hGH therapy. Current recommendations for r-hGH administration are 0.1 mg/kg subcutaneously daily (up to 8 mg daily) for a maximum of 4 weeks of therapy, beginning at least 6–12 months after onset of SBS (Steiger et al, unpublished data).17

Optimal Dietary and Medical Management
The ability of luminal nutrients to activate growth factors and stimulate pancreatic and intestinal peptide secretion for the promotion of adaptive intestinal hyperplasia is dependent on the composition of the diet.2,31 Strict compliance with dietary guidelines is therefore essential for the success of r-hGH treatment.14–16,18,23 Studies examining the effects of r-hGH without appropriate dietary modifications revealed no improvement in absorptive capacity of fluid, energy, nitrogen or electrolytes.20,22

Dietary management of patients with SBS should be customized according to the presence or absence of the colon.32 Patients with SBS may also benefit from the intake of small, frequent meals, limitation of simple sugars, possible addition of soluble fiber supplementation, and use of an isotonic, high-sodium beverage or oral rehydration solution to promote optimal fluid absorption (Matarese and Steiger, unpublished data).33 Hyperphagia with adequate fluid intake should be encouraged to ensure that daily nutrient and fluid requirements may eventually be met without IV support.34,35

Additionally, the dosage of antisecretory and antimotility agents should be optimized before initiating r-hGH treatment.36 Patients with SBS may require up to 4 times the generally recommended dosage of antidiarrheal therapy, and these medications should be taken 30–60 minutes before meals for maximum effect (Steiger et al, unpublished data).36 Baseline stool or stoma volumes should be ≤3 L per day while patients are eating or ≤800 mL per day with no oral food intake for r-hGH therapy to be successful.14

Adequate Nutrition Status
Before beginning treatment with r-hGH, a thorough nutrition assessment, including an assay of serum trace elements, plasma phospholipid fatty acid profile, and plasma fat-soluble vitamin status, should be conducted and any deficiencies should be corrected.37 Adequate nutrition status (defined as body mass index (BMI) ≥17 and absence of macro- or micronutrient deficiency) is critical for the synthesis of endogenous growth hormone and for the efficacy of exogenously administered growth factors.38,39 In return, both exogenous and endogenous growth factors enhance nutrient uptake and use by the small intestine.40 Additionally, an early study of intestinal adaptation after massive small bowel resection in dogs found an improved level of adaptation in dogs adequately nourished with PN.41 Dependence on a stable PN or IV fluid regimen for at least 3 months with intact nutrition status is therefore an important factor in the selection of patients most likely to respond to r-hGH therapy.

The use of r-hGH to avoid initiating PN in SBS patients has been studied in only 1 report.16 After a 4- to 6-week treatment with a specialized diet, behavior modification, medication, oral glutamine, and r-hGH, Byrne et al16 found that 9 of 12 patients (mean jejunal-ileal length = 114 cm) at high risk for PN were able to maintain their weight and fluid balance free of PN upon 1-year follow-up. Although the results are promising, this study did not have a control group to assess the outcome of an intensive intestinal rehabilitation program without r-hGH therapy, and the FDA has not yet approved the use of r-hGH in SBS patients not receiving PN.

Patient Education and Monitoring
All patients undergoing r-hGH therapy should be provided with detailed instructions and frequent reinforcement on all aspects of the rehabilitation effort.17 The rationale behind the therapies should be explained in order to promote improved compliance (DiBaise et al, unpublished data). Potential candidates for r-hGH should demonstrate ability to adhere to the appropriate diet, medication, and growth hormone regimen before initiating treatment. Patient education and behavior modification are important factors in determining the effectiveness of intestinal rehabilitation with r-hGH treatment.42 Careful monitoring of the SBS patient undergoing treatment with r-hGH is also essential to evaluate for any potential complications and side effects associated with the therapy (Table 3).


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  		Table 3 Monitoring of the SBS patient receiving r-hGH therapy

 


   Parameters for Weaning PN
Top
 Growth Hormone and Intestinal...
 Patient Selection
 Parameters for Weaning PN
Future Directions
 
After completing r-hGH treatment, patients must remain compliant with the diet and antimotility medication regimen to promote successful weaning or maintain independence from PN.15 In addition to compliance with the treatment regimen, patients will need to satisfy several criteria before PN delivery can be safely reduced (Table 4). Decisions regarding PN reduction should be made according to body weight, laboratory indices, intake and output records, and physical examination. Weaning from PN can be accomplished by either reducing the daily PN infusion volume or by decreasing the number of days that PN is infused, beginning with eliminating 1 day of PN per week (DiBaise et al, unpublished data). Days of the week in which PN is not infused should not occur consecutively until PN is required for only 3 days per week (DiBaise et al, unpublished data).


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  		Table 4 Criteria for reducing or transitioning patients off of PN

 

Patients will continue to need regular reinforcement and monitoring after maximal PN reduction in order to ensure maintenance of adequate nutrition and hydration status. One to 3 multivitamins per day and 1–3 g of supplemental calcium per non-PN day should be given orally during the weaning process. Sodium, potassium, bicarbonate, magnesium, phosphate, and trace elements should be supplemented orally to maintain normal serum values and normal acid-base balance. Intramuscular vitamin B12 injections (1000 µg/month) will be necessary upon weaning off PN if the terminal ileum is removed.

Enteral nutrition and hydration have recently been reported as an important adjunct to r-hGH therapy, which can aid in the process of weaning patients from PN.43,44 Enteral formula with optimal nutrient composition or oral rehydration solutions may be given continuously or nocturnally via a nasogastric or percutaneous endoscopic gastrostomy tube in SBS patients unable to meet nutrient and fluid requirements orally. Although this mode of feeding may add to the complexity of treatment, the goal of eliminating dependence on PN will free the SBS patient from risk of PN-related complications.


   Future Directions
Top
 Growth Hormone and Intestinal...
 Patient Selection
 Parameters for Weaning PN
 Future Directions
 
In 1997, an NIH advisory panel published recommendations calling for further research to evaluate the importance of growth factors in increasing residual intestinal mass and absorptive function in patients with SBS.45 Several studies demonstrating reduced PN requirements with only transient improvements in body composition have been conducted since then. It remains to be seen whether earlier initiation of therapy, longer treatment periods, or lower doses of r-hGH would prolong an increase in muscle mass or hasten the recovery of absorptive capacity in patients with SBS.

Fasting plasma citrulline levels have recently been shown to act as a marker of residual enterocyte mass in SBS patients.46,47 Plasma citrulline is a readily measured amino acid not incorporated into endogenous or exogenous proteins.48 Small bowel enterocytes function as the primary source of citrulline production through the glutamate-to-ornithine enterocyte pathway.49 Citrulline is not metabolized in the small intestine or liver but instead is converted into arginine in the kidney. Plasma citrulline also does not seem to be affected by nutrition status or dietary intake.46 The amount of plasma citrulline in circulation is therefore almost exclusively dependent on the remnant functional cell mass of the small intestine.

Crenn et al46 studied postabsorptive plasma citrulline levels of 57 SBS patients and found that a threshold of 20 µmol/L was able to discern transient from permanent intestinal failure. Permanent intestinal failure was defined as continued dependence on PN 2 years after final digestive circuit modification. Postduodenal remnant small bowel lengths measured by either radiograph films or during surgery equally correlated with plasma citrulline levels. Plasma citrulline concentration also correlated with net absorption of fat and protein, which was significantly greater in patients with transient vs permanent intestinal failure.

Seguy et al24 examined the change in plasma citrulline levels before and after administration of r-hGH in a study of 14 patients with SBS. A small increase in plasma citrulline was detected (from a mean of 18–20 µmol/L), indicating a possible shift from permanent to transient intestinal failure after 3 weeks of r-hGH therapy. Further research is needed in a larger study sample to confirm this trend and to investigate clinical response to r-hGH treatment in SBS patients with increasing plasma citrulline levels.

Quantifying remaining small bowel length and absorptive capacity remains a diagnostic challenge in assessing the clinical condition of patients with SBS. Further research tools like serum citrulline levels are needed to more clearly define the SBS patient's potential for rehabilitation and to provide objective measurements of the response to growth hormone therapy. The successful rehabilitation of patients with SBS requires the integrated multidisciplinary expertise of intestinal rehabilitation dietitians, gastroenterologists, surgeons, and home nutrition support clinicians working as a team in an institution supportive of an intestinal rehabilitation program.

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Nutrition in Clinical Practice, Vol. 20, No. 5, 503-508 (2005)
DOI: 10.1177/0115426505020005503
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