11.7 Artificial nutrition support 1914

11.7 Artificial nutrition support 1914

ESSENTIALS The prevalence and relevance of undernutrition in affluent societies is often unrecognized, but nutritional status significantly impacts out- comes in all disease states. Nutrition screening identifies patients at risk of undernutrition and should be carried out in hospitals and community: its components comprise past weight loss, current body mass index, and likely fore- seeable nutritional challenges. A body mass index less than 18.5 kg/​m2;
weight loss of more than 10% over 6 months; or BMI of less than 20 kg/​m2 with weight loss of more than 5% over 6 months, are all indicative of undernutrition. Nutrition support is indicated for malnourished patients or those at risk of undernutrition in view of inadequate oral intake or malabsorption. Timing of the intervention depends on the pre-​ existing nutritional status and the likelihood of restoring adequate intake. Nutrient requirements are calculated using weight-​based formulae for basal energy and protein requirements, with additional factors for physical activity, severity of illness, or desired weight gain. Increased requirements due to disease are often counterbalanced by reduced activity. Institutional provision of food (in a conducive environment) of appropriate quantity, texture, temperature, and variety, with encouragement and assistance to eat, may obviate the requirement for artificial nutrition support. Artificial nutrition support can be provided in the form of oral nu- tritional supplements, or enteral or parenteral tube feeding. Enteral feeding is physiologically preferable to parenteral nutrition as it maintains gut integrity, stimulates hormonal regulation of metab- olism and gastrointestinal functions, and delivers nutrients to the liver via the portal circulation. Tube feeding can be associated with significant complications re- lating to the means of access or delivery of nutrients. It is easy to overfeed with parenteral nutrition, especially in catabolic patients who are unable to utilize excess protein or energy. The potential risks of the route of feeding need to be balanced against the benefits for any individual, which influences the timing of the intervention. Tube feeding is only instituted where oral feeding is impossible or inadequate and hence benefits are unclear due to the ethical im- possibility of randomized trials in this setting. However, oral nutrition supplementation in selected patient groups is associated with signifi- cant reduction in both morbidity and mortality. A multiprofessional team is required to coordinate and monitor the necessary support for patients fed artificially in hospital and the community. Patients can receive artificial nutrition support indefin- itely in the community. Outcomes of intestinal transplantation have improved significantly over recent years, but due to excellent long-​ term outcomes on home parenteral nutrition, this is usually con- sidered only where there are life-​threatening complications of such treatment. Introduction In affluent societies where food is plentiful the extent of under­ nutrition is poorly recognized, affecting more than 10% of all adults over the age of 65 years in the community, and around 40% of all hospital inpatients or elderly care home residents. Undernutrition usually arises from social or disease-​related factors, and in turn has profound implications for the progression of illness and outcome of treatment by altering physiological responses and having effects on immunity and healing as well as psychology, motivation, and social interaction. Chronic illness often increases nutritional require- ments, but this is often balanced by a reduction in physical activity. The associated anorexia or inability to feed orally usually contrib- utes more significantly to undernutrition and is directly amenable to intervention by nutrition support. Nutritional screening and assessment of nutritional status Weight is easier to lose than regain, and although weight may be ul- timately restored, the body composition takes longer to normalize as initial weight gain comprises significant fluid and fat components rather than lean mass. The risk of undernutrition related complica- tions therefore relates to the disease trajectory as well as the current nutritional status. These components—​prior weight loss, current nutritional status, and pending threats to nutritional intake—​are combined into a nutrition ‘risk score’, and such scores are routinely 11.7 Artificial nutrition support Jeremy Woodward

11.7  Artificial nutrition support 1915 used in clinical practice to identify patients requiring nutritional op- timization (Fig. 11.7.1). History A nutrition history will include the nature of the baseline diet—​not only for vegans and vegetarians who may be lacking in haem iron and vitamin B12, but also for poor fresh fruit and vegetable intake (vitamin C and folic acid) and dairy avoidance (calcium), or other dietary restrictions due to intolerances, dislikes, or fads. Excessive alcohol intake can be associated with thiamine and folic acid deficiency. Oral conditions may make ingestion painful; abdominal symp- toms such as nausea, bloating or pain can reduce intake and patients may not admit to (or even be aware) of significant changes in appe- tite. Medication side effects may alter dietary intake and a variety of conditions can lead to taste disturbances. Psychosocial circumstances can have a profound impact on oral intake—​for instance, in depres- sion, bereavement, social isolation, impaired mobility, or poverty. Fig. 11.7.1  The ‘Malnutrition Universal Screening Tool’ (MUST)—​an example of an algorithm for screening and identification of malnutrition and the appropriate actions to be taken based on risk score. This tool is reproduced with kind permission of BAPEN—​British Association for Parenteral and Enteral Nutrition.

SECTION 11  Nutrition 1916 Examination Patients may not have weighed themselves or be aware of weight loss, but clinical features may be present such as prominent cheek- bones, muscle wasting, redundant skin folds, and concave abdomen. Ill-​fitting clothing, belt notches, and loose rings on fingers provide additional clues. Many of these signs are apparent even in obese in- dividuals who remain overweight despite recent weight loss. Signs of specific nutritional deficiencies (see Chapters 11.2 and 11.3) may be identified, particularly in hair, eyes, skin, nails, teeth, and tongue. Body mass index, and its limitations The ratio of weight (in kg) to the square of the height (in m2) is known as the body mass index (BMI) and provides a useful indication of nutritional status. It may, however, be misleading, for instance in younger patients, those with skeletal deformity due to cerebral palsy, or elderly patient with osteoporosis. A BMI of less than 18.5 kg/​m2 is considered indicative of undernutrition, as is weight loss of more than 10% over 6 months or a BMI of less than 20 kg/​m2 in associ- ation with weight loss of more than 5% over 6 months. In children the use of centile charts is valuable as sustained undernutrition leads to reduced height velocity and failure to meet predicted height. The major drawback of using BMI for nutritional assessment is that it is affected by changes in body composition, with clinically important changes in lean body mass being masked by shifts in fluid distribution and adipose tissue. The entity of sarcopenic obesity—​ overweight individuals with reduced muscle mass or function—​has recently been described associated with ageing or inflammatory pathology and highlights the weakness of using body mass alone without considering its components. Bio-​impedance measurement can provide measurements of extra- cellular water and estimates of fat-​free mass from which lean body mass can be calculated, but validation in disease settings is still re- quired. Sequential measurements of mid-​upper arm circumference and triceps skin fold thickness using a tape measure and callipers can provide estimates of changes in lean body mass, and hand-​grip dynamometry measurements are a useful surrogate of changes in functional muscle mass. Used at a single point in time, however, wide reference ranges make these tools unreliable for nutritional assessment. Dual energy X-​ray absorptiometry (DEXA) and volu- metric analysis of CT scans are becoming more widely available as tools for measuring body composition. Indications for artificial nutrition support Undernutrition can be prevented in patients at risk by simple meas- ures to optimize appetite such as reducing symptoms such as pain or nausea that lead to anorexia. The range of menus and the presen- tation and temperature of meals in hospital affect the amount con- sumed, as well as limiting interruptions at mealtimes or ‘nil by mouth’ orders. Institutional catering needs to accommodate the require- ments of patients with altered feeding patterns, such as after upper gastrointestinal surgery or with dysmotility, and older people often prefer to snack rather than take large meals. Patients with disabil- ities may require assistance with eating and sufficient staff and time are required to provide this. Food texture may need to be altered—​ pureed or liquid diets benefit patients with oesophageal strictures or gastroparesis, whereas thickening fluids with starch reduces the risk of pulmonary aspiration in neurological causes of dysphagia. Artificial nutrition support is required if such measures are in- effective in maintaining sufficient oral intake. If swallowing is in- tact and palatability is acceptable then oral nutrition supplements can be provided. Unconscious patients, those unable to swallow or with upper gastrointestinal obstruction can receive enteral nutrition support if intestinal function is preserved. Access can be achieved by pernasal or transabdominal feeding tubes to the stomach or in- testine. Patients without adequate intestinal function require total or partial parenteral nutrition support via an intravenous catheter. Common indications for enteral and parenteral artificial support are given in Tables 11.7.1 and 11.7.2. The timing of nutritional support interventions depends on the pre-​existing nutritional status of the patient and likely subsequent events. It has proven difficult to demonstrate any benefit for short term artificial nutrition support, but it is equally challenging to predict when a patient will become nutritionally independent. Table 11.7.1  Common indications for enteral nutrition support Impaired conscious level Head injury Ventilated patients in critical care setting Cerebrovascular disease Neurological dysphagia Motor neuron disease Cerebrovascular disease Multiple sclerosis Bulbar palsy Cerebral palsy Upper gastrointestinal obstruction Head and neck cancer Oesophageal cancer Gastric cancer Gastric outlet obstruction—​benign or malignant Dysmotility Severe oesophageal dysmotility Gastroparesis Related to treatment modalities Prior to chemoradiation therapy for head and neck cancer Post complex upper gastrointestinal surgery
(i.e. Whipple’s procedure, oesophagectomy) Inability to meet nutritional requirements orally Malabsorption Borderline short gut Anorexia secondary to chronic illness Respiratory disease (i.e. cystic fibrosis) Table 11.7.2  Common indications for parenteral nutrition support Enteric dysmotility Hirschsprung’s disease Visceral neuropathy Visceral myopathy Systemic sclerosis Radiation enteritis Postoperative ileus Intestinal obstruction Malignancy –​ Gastrointestinal –​ Metastatic ovarian or peritoneal –​ Metastatic breast Sclerosing peritonitis Postsurgical adhesions Mucosal disease Microvillous inclusion disease Autoimmune enteropathy Refractory coeliac disease

11.7  Artificial nutrition support 1917 However, the benefits of early nutrition support have been clearly demonstrated in a variety of settings and the timing of intervention therefore requires an individual assessment balancing the benefits of early intervention against its cost and risks. Estimating nutrition requirements Energy Energy expenditure under basal conditions reflects physiological cellular metabolism and therefore correlates with body mass. Derivative equations based on weight and corrected for age and gender provide estimates of energy consumption that adequately match measurements based on oxygen uptake and CO2 production (indirect calorimetry) for most clinical purposes. Additions are re- quired for activity and the thermal effect of food. Disease states such as burns, sepsis, or trauma increase energy expenditure, but this is usually compensated for by reduced physical activity and overall may equate to an increase of only 10–​20% over resting energy ex- penditure. Corrections also need to be made for patients with oe- dema or obesity and energy requirements in these circumstances may be based on a proportion of body mass or ideal body weight. Most hospital patients’ requirements lie within the range of 25–​40 kcal/​kg per day (105–​168 kJ/​kg per day). Fluid Fluid balance must be considered a part of the nutritional require- ments, and nutrition and hydration should be considered together. Most hospitalized patients require 30–​35 ml/​kg per day, with add- itions to replace losses. Fluid losses from the kidneys—​with diabetes insipidus or when recovering from acute tubular necrosis—​can be excessive and obligatory, while volumes of 10 litres a day can be lost from the gastrointestinal tract via a proximal jejunostomy or enterocutaneous fistula. Fluid restriction is indicated in overloaded states or in renal or cardiac failure and diluents for intravenous drugs and line flushes can reduce the fluid allowance available for the feed in ill patients. Most enteral feeds provide 1 kcal/​ml but specialized feeds with up to 2 kcal/​ml are available for such circumstances. Electrolytes Average requirements for sodium and potassium are of the order of 1 mmol/​kg per day for most adults. However, significant losses of sodium and other electrolytes can occur through the gastrointes- tinal tract (Table 11.7.3), and potassium deficits may also be large in patients receiving thiazide diuretics, during recovery of metabolic acidosis, and during refeeding of severely underweight individuals. Phosphate requirements increase greatly during refeeding from a baseline of approximately 0.3 mmol/​kg per day. Feeds with minimal electrolyte content are required in oliguric renal impairment where solute clearance is reduced, but the com- monest cause of excessive electrolyte administration in hospitals is the inappropriate use of normal (0.9%) saline, which contains 154 mmol/​litre of sodium, and salt-​rich colloid solutions for main- tenance fluid requirements. Macronutrients Protein Protein is required to meet obligatory catabolic losses (minimal requirement) and to stimulate protein synthesis (optimal require- ment). The World Health Organization (WHO) recommendation of minimal requirement is 0.75 g protein/​kg per day (0.12 g N/​kg per day) based on nitrogen balance studies on a protein-​free diet (Fig. 11.7.2). Increasing the dietary protein intake will increase pro- tein synthesis in depleted patients as long as sufficient calories are taken, and the optimal calorie:nitrogen ratio may vary depending on the disease state. Although net protein synthesis can be achieved by increasing dietary protein in undernourished patients, the same is not true in the catabolic state induced by sepsis, burns, or trauma, where excess amino acids can exert detrimental effects. Intakes of above 1.5 g protein/​kg per day (>0.24 g N/​kg per day) are not gener- ally recommended. Amino acids have physiological roles beyond protein synthesis and individual amino acid levels vary significantly between dif- ferent disease states. Most artificial feeds provide standard amino acid solutions that do not cater for such differences and may result in relative imbalances of amino acid that could compromise amino acid utilization. Histidine levels are low in renal impairment, and branched chain amino acids (valine, leucine, isoleucine) are reduced in chronic liver disease. Glutamine is significantly depleted in crit- ical illness and improvement in nitrogen balance has been demon- strated with supplementation. An important demonstration of amino acid imbalance affecting protein synthesis is the (diagnostic) rise in blood urea associated with an upper gastrointestinal haemorrhage. While previously thought to be associated with an excess nitrogen load absorbed from the protein in the ingested blood, it appears that the cause is the lack of isoleucine residues in haemoglobin that leads to a relative deficiency of isoleucine in the circulation which thereby inhibits protein synthesis. The rise in urea is endogenous, due to the ongoing breakdown of protein without utilization of resultant amino acids in protein synthesis, and can be abrogated by simultan- eous isoleucine infusion. Table 11.7.3  Electrolyte composition of gastrointestinal fluids (in order to calculate replacement of losses) Fluid Na+ (mmol/​litre) K+ (mmol/​litre) HCO3 –​ (mmol/​litre) Cl–​ (mmol/​litre) Volume (/​24 h) Gastric juice 60 15 –​ 90 2500 Pancreatic juice 140 5 90 75 1500 Bile 140 5 35 100   500 Small intestinal contents 100 10 25 100 1000 (Succus entericus) Diarrhoea 60 30 45 45

SECTION 11  Nutrition 1918 Carbohydrate Carbohydrates should make up 50–​65% of calories in a healthy diet. In excess of 5 g/​kg per day, glucose is stored as glycogen up to a max- imum storage capacity of 15 g/​kg. Continued administration of glu- cose results in lipid synthesis and hepatic steatosis. Maximal glucose oxidation rates are frequently lower in disease states due to insulin resistance and excessive glucose administration can therefore result in hyperglycaemia. Lipid The lower limit constraint on lipid provision is the need for essential fatty acids (linoleic and α-​linolenic acids), which can be provided in 3–​4.5% of the total energy requirements as fat. Lipid is used in artificial nutrition to provide the energy that cannot be supplied as carbohydrate due to the limit of glucose oxidation. The amount of CO2 produced by oxidation of lipid is 30% less than that of glucose, which could theoretically help patients with respiratory failure or weaning from a ventilator, but clinical benefits are small in practice. Micronutrients Vitamins A balanced diet provides sufficient vitamins in most cases. There are no body stores of the water-​soluble B vitamins, which can be de- ficient in a variety of different disease states including alcoholism, recurrent vomiting, and diabetes. Vitamin B12 is only present in animal dietary sources and therefore those following a vegan diet are prone to deficiency. Vitamin deficiencies can have profound ef- fects on cellular metabolism and few vitamins are toxic in excess, hence vitamin levels in commercial feed preparations generally ex- ceed estimated requirements. This excess helps to compensate for the degradation of some vitamins that occurs in solution—​vitamin A  and riboflavin are photosensitive (hence the need to protect hanging parenteral nutrition solutions from the light), thiamine reacts with preservatives required to maintain shelf life in paren- teral nutrition, and vitamins C and E are ineffective when oxidized. The latter is used in excess in parenteral nutrition to prevent lipid peroxidation. Vitamin K is normally not required in artificial nutrition, due to enteric bacterial synthesis, and its addition could affect therapeutic anticoagulation. Biotin (vitamin B7) and pyridoxine (vitamin B6) are also made by enteric bacteria. The latter has been associated with a reversible toxic neuropathy if taken in excess. Fat soluble vitamins—​ A, D, and E—​can be provided in a water-​miscible solution in paren- teral nutrition. Minerals and trace elements In contrast to vitamins, toxicity is associated with excess delivery of some trace elements. The enterocyte regulates iron uptake and rela- tively small amounts of trace elements are absorbed from the intestine, hence overadministration is more likely to occur with parenteral than with enteral nutrition. Manganese and copper undergo biliary ex- cretion and accumulation can occur in parenterally fed patients with cholestasis: basal ganglia deposition can be detected on brain MRI scanning, but neurological effects are rarely reported. Chromium is excreted through the kidneys and can accumulate in renal failure, but toxic effects have not been reported. Zinc is lost through the intestine in high output states and in wound exudates leading to requirement for supplementation. Selenium plays a key role in cellular redox main- tenance as a cofactor in glutathione peroxidase and some authorities recommend supplementation in critical illness. Analysis of trace element levels in the blood can be inaccurate and affected by the acute-​phase response and serum albumin con- centration, and interpretation of low levels is always complicated by the possibility that it reflects a physiological response to acute illness such as in the case of iron sequestration in infection. Complications of artificial nutrition support The ease with which full nutrition requirements can be delivered by artificial means results in a risk of ‘refeeding syndrome’ on initiating feeding in chronically undernourished patients. Features include elec- trolyte imbalance (hypokalaemia, hypophosphataemia, hypomagnes- aemia) and an associated risk of cardiac arrhythmia and sudden death, hyperglycaemia, and fluid shifts that can precipitate heart failure. The rapid depletion of thiamine—​an essential cofactor of pyruvate decarboxylase—​results in inhibition of glycolysis on refeeding and damage to glucose dependent cells such as neurons, the clinical pres- entation of Wernicke–​Korsakoff syndrome. This is preventable by the administration of high-​dose intravenous thiamine prior to refeeding (or glucose administration) in patients considered at risk. Other complications of artificial nutrition support are specific to the route of delivery. Access devices in common use, with their ad- vantages and disadvantages are listed in Table 11.7.4. 0.5 0.4 0.3 0.2 0.1 Nitrogen intake (g/kg/day) Nitrogen balance (mg/kg/day) 200 160 120 80 40 40 80 120 160 200 + − Severe nutritional depletion Moderate nutritional depletion No nutritional depletion No nutritional depletion: Severe injury Fig. 11.7.2  Relationship of nitrogen intake and nitrogen balance in patients receiving sufficient energy. Normal subjects reach nitrogen balance at approximately 0.1 g/​kg/​day nitrogen intake; positive nitrogen balance can be achieved in malnourished patients. Severe illness (trauma, sepsis, burns) results in net catabolism. Patients with a combination of depletion and severe illness react in an intermediate fashion. Reprinted from Clinical Nutrition, Vol. 1. Elia M, ‘The effects of nitrogen and energy intake on the metabolism of normal, depleted and injured man: Considerations for practical nutritional support’, pp. 173–​92, Copyright © 1982, with permission from Elsevier.

11.7  Artificial nutrition support 1919 Table 11.7.4  Types of enteral and parenteral access devices in common use Type of tube Description Use Advantages Disadvantages Enteral (EN) Nasogastric Fine-​bore (6–​8 F) polyurethane tube; can be secured with a nasal bridle—​a loop of tape around the nasal septum Short-​to-​medium term intragastric feeding due to inability to swallow, nutritional supplementation; bolus or infusion feed Bedside placement without sedation; well tolerated Risk of malposition; difficult to manage in confused patients Nasojejunal Fine-​bore polyurethane tube with tip passed into distal duodenum/​proximal jejunum Inability to swallow complicated by gastro-​oesophageal reflux or gastroparesis; gastric outlet obstruction; acute severe pancreatitis Can be placed non​invasively at bedside; accurate delivery into proximal intestine. Infusion feed only May require endoscopy or fluoroscopy for placement; easily displaced PEG (percutaneous endoscopically placed gastrostomy) Tube passed through abdominal wall into stomach using an endoscopic technique (‘push’ or ‘pull’). Retained internally by balloon or internal bumper/​disc. Available in sizes up to 24 F Long-​term intragastric feeding; mucositis due to head and neck cancer therapy; palliative venting use in terminal intestinal obstruction Difficult to displace; reliable in long-​term use; can be exchange for skin level (‘button’) device, ideal for ambulant or younger patients Requires endoscopic placement and endoscopy to change tube. Early complications include peritonitis, bleeding, PEG site infection. Late complications include overgranulation of the PEG site and ‘buried’ bumper (see Fig. 11.7.3) RIG (radiologically placed gastrostomy) Radiologically placed transabdominal gastrostomy tube Intragastric feeding where endoscopic placement is not possible due to risks of endoscopy or anatomical considerations Can be a safer option than standard PEG in some patients Requires gastric insufflation through a nasogastric tube which may not always be possible to place. Some centres report higher numbers of significant complications with RIGs than PEGs PEG-​J (PEG with jejunal extension) Transgastric tube with tip positioned in distal duodenum/​proximal jejunum through existing PEG tube Long-​term intestinal feeding where gastric feeding is not available due to gastric dysfunction o outlet obstruction Minimally invasive route for long-​ term postpyloric feeding Jejunal tube can reflux back into the stomach DPEJ (direct percutaneous enteroscopic jejunostomy tube) PEG tube placed endoscopically into the jejunum Long-​term intestinal feeding Reliable for long-​term feeding Endoscopic placement not always possible. High risk of complications including pain and volvulus (given single point of contact of intestine and abdominal wall) Surgical jejunostomy Feeding tube placed surgically into the jejunum Postoperative feeding in upper gastrointestinal surgery and liver transplantation Permits early enteral feeding in postoperative setting Not ideal for long-​term use due to risk of displacement and adhesional obstruction Parenteral (PN) Midline catheter Short peripheral (22 G) cannula inserted into antecubital vein Short term parenteral nutrition support May allow effective peripheral nutrition support or supplementation without risks or delays of central venous access Limited range of available feeds due to the osmolality and pH considerations which usually limits use of this route to 2–​3 days PICC (peripherally inserted central venous catheter) ‘Long-​line’—​tube placed via the cephalic vein into large central veins Short-​to-​medium term parenteral nutrition support (suitable for majority of inpatient PN episodes) Reduced risk of infection and generally preserves central access points Thrombophlebitis and thrombosis. Not practical for use at home or by patients Triple lumen venous catheter Multiple lumen direct puncture central venous catheter Fluid and drug delivery—​central venous pressure monitoring Ease of access in critically ill patients High risk of local complications and infection. Should be discouraged for parenteral feeding except in time limited circumstances with a dedicated lumen to PN Tunnelled Hickman catheter Single or double lumen line tunnelled subcutaneously to the skin surface with a Dacron cuff for retention Medium-​long-​term parenteral nutrition support Low risk of infection if properly maintained; low risk of displacement once cuff is grown in Care needed with the external portion to avoid accidental displacement. Risk of exit site infection or mechanical dysfunction Implantable subcutaneous port device Line accessed via a hub placed in a subcutaneous pocket—​no part of the device visible above skin level Long-​term parenteral nutrition support Ideal for patients with active lifestyle—​evidence of different rates of line infection compared to tunnelled lines is controversial Skin puncture required for every access; consequences of infection more significant than with tunnelled line—​more difficult to replace. Limited lifetime of membrane depending on the frequency of puncture

SECTION 11  Nutrition 1920 Enteral Complications of access Incorrectly placed nasogastric tube can kill. Inadvertent intra­ pulmonary placement is the most frequent, but insertion into cra- nial, pleural, and peritoneal cavities has occurred. Feeding should only be initiated after confirmation of gastric placement by pH meas- urement of aspirated stomach contents (<5.5) or by radiography. Interruptions due to frequent tube displacement causes a signifi- cant reduction in feed delivery—​as little as 55% of prescribed feed in one study. This can be prevented by the use of a loop of tape that can be safely and simply passed around the nasal septum to secure the tube (‘nasal bridle’). Modern tube material does not cause sig- nificant erosion or irritation of the face, nares, or mucosal surfaces, even with long-​term use, but difficulties in managing such tubes in the community make them undesirable for long-​term use. Transabdominal feeding tubes are therefore used in preference in the community for enteral feeding. Percutaneous endoscopically guided (PEG) tubes are most frequently employed, but a variety of tubes can be placed endoscopically, radiologically, or surgically into the stomach or proximal intestine (Fig. 11.7.3). There is a high risk of death following placement due to cardiorespiratory complications in patients who are at high risk due to dysphagia and pre-​existing pneumonia. Asymptomatic pneumoperitoneum is common after PEG insertion, but chemical peritonitis can result from feed leakage into the peritoneal cavity. Superficial infections at the PEG site should occur in less than 5% of cases: these are usually easily treated but should not be confused with chemical burns due to leakage of enteric contents. Skin swabs are rarely useful in suspected PEG site infection. Too much tension on the device can lead to erosion of the internal retaining bolster into the gastric mucosa and through the abdominal wall (‘buried bumper’), leading to blockage, external feed leakage and infection, and may only be apparent on attempted PEG removal. Complications of enteral feeding The role of the intestine in regulating nutrient uptake is demon- strated by the reduced metabolic complications of enteral compared (a) (c) (b) Fig. 11.7.3  (a) A range of endoscopically placed gastrostomy tubes—​from left to right—​bumper-​retained gastrostomy; traction-​removable bumper-​retained gastrostomy; balloon retained gastrostomy; skin level ‘PEG-​button’ device (balloon retained). (b) Endoscopic photograph of PEG tube with bumper in place in the stomach. (c) ‘Buried bumper’—​the bumper of the gastrostomy has eroded into the gastric mucosa as a result of pressure necrosis and the mucosa has overgrown the bumper. A wire has been passed through the lumen of the tube to demonstrate its position.

11.7  Artificial nutrition support 1921 to parenteral feeding: nutritional deficiencies in patients fed appro- priately with commercial preparations are highly unusual. Patients who require enteral feeding often have impaired con- scious level or swallowing and are therefore at risk of pulmonary aspiration. Delayed gastric emptying—​as frequently occurs in crit- ical illness—​increases the likelihood of aspiration of stomach con- tents. Gastro-​oesophageal reflux may be exacerbated rather than reduced by PEG feeding. Patients at risk should be fed by infusion pump rather than intermittent bolus and at a 30-​degree tilt. Passage of a feeding tube beyond the pylorus is beneficial in cases of delayed gastric emptying or gastric outlet obstruction. Diarrhoea is common in enterally fed hospital patients and is often due to the concomitant use of antibiotics. Liquid feed emp- ties rapidly from the stomach compared to solids and can result in an osmolar load that precipitates fluid influx and intestinal hurry, and neuroendocrine mechanisms have been described that result in right colonic fluid secretion with nasogastric feeding. Constipation may be encountered more frequently in enterally fed patients in the community:  fibre-​supplemented feeds are available for such instances. Parenteral Complications of access Intravenous feed should not be delivered via peripheral cannulae due to the risk of thrombosis and thrombophlebitis, and available preparations are constrained by pH and osmolality requirements. Central venous access is required for longer-​term parenteral nutri- tion but carries attendant risks of pneumothorax and haemothorax on placement. Peripherally inserted central lines can be used suc- cessfully for feed delivery, and arteriovenous fistulae for renal dia- lysis have also been used successfully in this setting. Infection is the major hazard of intravenous feeding catheters and is reduced by dedicating a single lumen to the feed and employing strict aseptic precautions. Use of opiates, presence of a stoma, and frequent line access are risk factors for infection. Tunnelled or peripherally inserted lines should be used in preference to non-​ tunnelled central lines. Staphylococci, Gram-​negative bacilli, and candida are common infecting organisms. Infection can present insidiously with low grade fever and result in complications by dissemination such as bacterial endocarditis, discitis, osteomyelitis, or fungal endophthalmitis. Catheter-​related infections are infrequent in longer-​term commu- nity parenteral nutrition, with infections occurring on average every 2 to 5 years. Venous thrombosis associated with frequent line replacement may limit options for access and require creative solutions such as direct translumbar or transhepatic caval access, intra-​atrial access, or surgical reconstruction of venous anatomy. Complications of parenteral feeding Metabolic complications are more likely to arise as a result of paren- teral than enteral feeding for the following reasons: • Parenteral feeding bypasses the enterocyte which actively regu- lates uptake, metabolizes nutrients, and re-​exports them via the portal circulation. • Insulin, glucagon, and incretin secretion (as well as that of other entero-​endocrine hormones) that regulate metabolic processes and disposal of nutrients from the circulation are controlled by the presence or absence of nutrients in the gut. • Parenteral feeds cannot replicate the complexity of circulating nu- trient molecules, being constrained by requirements of chemical stability within the solution. The metabolic risks of parenteral nutrition have previously been overestimated due to the ease of overnutrition via this route and de- liberate ‘hyperalimentation’. Hyperglycaemia is especially common due to insulin resistance associated with critical illness and re- sults in increased infection and adverse outcomes. Imbalances of other nutrients may occur as a result of variable losses associated with the underlying condition and require regular monitoring and replacement. The gut derives a proportion of its nutrient requirements from the lumen rather than the bloodstream, hence parenteral nutrition may result in mucosal atrophy and impaired barrier function. Although physiological and anatomical changes have been described, adverse consequences due to bacterial translocation appear to be rare from this cause in clinical practice. Intestinal-​failure-​associated liver disease Hepatic complications are commonly described in patients receiving parenteral nutrition. Asymptomatic elevation of liver enzymes indi- cative of cholestasis occurs after about 4 weeks of feeding via this route, but can progress to profound jaundice and cirrhosis, espe- cially in children. Intestinal-​failure-​associated liver disease tends to progress more insidiously through hepatic steatosis to cirrhosis in adults. Causes are likely multifactorial, including a reduced portal inflow due to short bowel syndrome and lack of enteric stimula- tion of cholecystokinin release. Several factors associated with par- enteral feed have been implicated in both excess and deficiency (Table 11.7.5). Maintaining oral intake, even if contributing only minimally to nutrient requirements, using cyclical rather than con- tinuous feed, and keeping exogenous lipid delivery under 1 g/​kg per day appears to reduce the risk of developing liver disease. The use of new lipid substrates containing fish oil and rich in omega-3 lipids appears to be preferable to the use of older soy-oil based preparation. Intestinal-​failure-​associated bone disease Metabolic osteopenia is common in intestinal failure requiring long-​term parenteral nutrition. Prolonged bed rest, immobiliza- tion, and vitamin D malabsorption contribute prior to the initiation Table 11.7.5  Aetiological factors implicated in intestinal-​failure-​ associated liver disease (IFALD) Cholestasis Steatosis Reduced enteral stimulation Excess provision of calories as carbohydrate or lipid Phytosterols present in soy-​based formulae Choline deficiency Infection Carnitine deficiency Bacterial translocation Reduced very low-​density lipoprotein synthesis Taurine deficiency Inadequate Glucagon secretion Methionine deficiency

SECTION 11  Nutrition 1922 of parenteral nutrition. A low bone turnover state has been rarely described. Careful monitoring of bone density and treatment with intravenous bisphosphonates is often required. Long-​term artificial nutrition support and intestinal transplantation Long-​term artificial nutrition support Patients can receive oral, enteral, or parenteral nutrition support in the community. In the United Kingdom, the British Artificial Nutrition Survey (BANS) carries out an annual survey of the number of tube-​fed patients. Approximately 350 per million British adults receive enteral tube feed in the community, compared to about 40 per million receiving parenteral nutrition at home. The latter has increased significantly over recent years due to improvements in homecare provision and a recognition of previous underutilization leading to patchy uptake across the United Kingdom. Quality of life is often adversely affected by the underlying dis- ease process more than the route of artificial nutrition support, but infusing feed overnight can minimize lifestyle disruption. Life ex- pectancy is also mostly dictated by the underlying disease process, with relatively few deaths attributed to failure of feeding or compli- cations of delivery. Ten-​year survival on long-​term home parenteral nutrition is approximately 59–71% in adults and 81% in children. The patients receiving enteral nutrition at home tend to be more eld- erly and infirm than those receiving parenteral nutrition and have a survival of around 25% at five years. Intestinal transplantation Patients with irreversible intestinal failure who experience life-​ threatening complications of parenteral nutrition can be con- sidered for intestinal transplantation, which can be combined with other abdominal organs where required for reasons of asso- ciated organ failure or anatomical considerations. Multivisceral transplantation including liver, stomach, intestine, pancreas, and colon may be required for patients with complications of exten- sive portomesenteric thrombosis, or urgently in acute abdominal ischaemia. Transplantation of the ileocecal valve and a segment of colon along with intestine is now routine to improve fluid absorp- tion postoperatively. Most patients undergoing intestinal transplant can become in- dependent of artificial nutrition support, and survival rates are now equivalent to—​or better than—​those of other solid organ transplant operations (Fig. 11.7.4). However, the operation is currently not considered as a routine alternative to home paren- teral nutrition, which is associated with excellent long-​term out- comes, although it may offer benefits in some cases. There is a realistic prospect that further improvements in the field will re- sult in better identification of cases that would benefit from earlier transplantation. Ethics of artificial nutrition support Nutrition and starvation evoke emotive responses, but although it is a basic human right not to be deprived of fluid or food, the same is Patient three-year survival, including super urgent patients, following first intestinal transplant, by ITR group, for patients transplanted between 1 February 2006 and 31 December 2015 at Cambridge transplant unit MMV SB MVT Transplant type MMV MVT SB Total 12 100 90 80 70 60 50 40 30 20 10 0 0 1 2 Years post-transplant % patient survival 3 34 12 58 1 14 2 17 89 (43–98) 62 (32–69) 81 (42–95) 65 (60–77) No patients No deaths % Patients survival (95% confidence interval) Transplanted and follow-up data were extracted from the UK Transplant Registry on 14 April 2016 Fig. 11.7.4  Survival post intestinal transplant. SB, small bowel transplant; MVT, multivisceral transplant (stomach, pancreas, liver, intestine, colon); MMV, modified multivisceral transplant (stomach, pancreas, intestine, colon). Source: NHSBT, courtesy Cambridge University Hospitals NHS Foundation Trust, 2016 data.

11.7  Artificial nutrition support 1923 not true of artificial nutrition support which requires invasive tube placement that may be associated with risks of morbidity or mor- tality. Ethically, withdrawing or withholding artificial nutrition are considered equivalent, but in practice it is often difficult to cease feeding when established through a tube, and the progress of an underlying condition can be affected by the continued delivery or withdrawal of feed. Institution of artificial nutrition support there- fore requires careful multidisciplinary discussion and appropriate patient and carer information in order to identify appropriate goals and expectations of feeding. Special situations in nutrition support Critical illness—​burns, trauma, and sepsis The metabolic response to stress is characterized by hypermetabolism and rapid tissue catabolism with resulting insulin resistance and hyperglycaemia. Direct effects of inflammatory mediators and cyto- kines such as tumour necrosis factor–​α and interleukins 1 and 6 are responsible. Protein loss can be rapid, particularly in the case of burns where exudates add to catabolic loss. Feeding during acute metabolic decompensation can be detri- mental and should be withheld during such time. Otherwise, early institution of feeding has been shown to be beneficial in most set- tings, with a graded increment to meet requirements and avoid overfeeding. Gastric stasis is common after severe burns and head injury and intestinal ileus may occur in circulatory failure requiring inotropic support. Prokinetic use may assist gastric emptying of en- terally delivered feed, but where gastric aspirate volumes remain high or increase during intragastric feeding, postpyloric or paren- teral feeding may avoid the risk of pulmonary aspiration and ensure adequate nutrient delivery. Avoidance of underfeeding is also important in critical illness and relies on appropriate recognition of the transition from a catabolic to anabolic phase. Attempts to reverse catabolism using inhibitors of inflammatory cytokines or anabolic agents have unfortunately been unsuccessful. Nutrients themselves may be used to modulate inflammatory responses, such as the use of lipid substrates enriched with omega-​3 fatty acids, and encouraging results have been demon- strated in sepsis and postsurgery. Renal disease Renal failure results in wasting, electrolyte and fluid imbalances, and anorexia with attendant malnutrition. Patients undergoing dialysis lose protein into the dialysate—​up to 10 g/​day on haemodialysis and up to 15 g/​day on peritoneal dialysis. Water-​soluble vitamins are also lost in the dialysate and require replacement. Adequate pro- tein intake is essential to minimize catabolism of endogenous pro- tein. Specialized feeds with minimal electrolytes and reduced fluid volume are available for renal patients (Table 11.7.6). Parenteral nu- trients may be infused to replace losses at the time of dialysis. The use of reduced (but high-​quality) protein feeds may delay the re- quirement for dialysis in renal failure but this should not be at the expense of inadequate nutrition support. Liver disease Malnutrition is common in patients with established liver dis- ease as a result of reduced appetite, altered carbohydrate and lipid metabolism, and (in severe cases) impaired urea synthesis from ammonia leading to increased muscle catabolism. Cholestasis also results in fat malabsorption. Glucose intolerance limits glu- cose intake and complex polysaccharides are required to provide a slow release of carbohydrates in view of diminished glycogen stores. The lack of carbohydrate stores in the liver makes patients prone to significant protein catabolism during fasting and there- fore periods without nutrient intake—​even overnight—​should be avoided. High protein feeds may precipitate encephalopathy in cirrhosis, but restricting protein is nutritionally undesirable and an intake of 1.2–​1.5 g protein/​kg per day is recommended. Optimization of the amino acid composition—​by enriching with branched chain amino acids which are deficient in liver disease—​can improve protein syn- thesis and result in improved survival for patients with end stage liver disease awaiting transplant. Table 11.7.6  Examples of disease-​specific and therapeutic feeds designed to have disease modifying activity (‘nutraceuticals’) Composition Intended use Rationale Low protein, high essential amino acids, and histidine, low electrolytes, high calorie density Renal impairment Appropriate matching of amino acid composition to requirements may improve protein metabolism; low protein reduces urea synthesis; high calorie density allows fluid restriction Low protein, reduced aromatic and increased branched chain amino acids, low sodium Hepatic impairment Reduced risk of encephalopathy with low protein; appropriate amino acid mix to allow optimal protein metabolism High lipid, low carbohydrate Pulmonary disease; weaning from artificial nutrition Reduced CO2 production High lipid (especially monounsaturated fatty acids); low carbohydrate, high fructose Diabetes Reduced glycaemia, improved diabetic control Oligopeptides, medium chain triglycerides Severe pancreatic exocrine deficiency Reduced dependence on luminal digestion for absorption Arginine, n-​3 fatty acids, nucleotides ‘Immune enhancing’—​critical illness/​perioperative nutrition Substrates for rapidly dividing cells such as lymphocytes and competitive inhibition of proinflammatory eicosanoid production may enhance immune response and reduce inflammatory response Glutamine Critical illness Glutamine levels severely depleted in critical illness; supplementation may improve nitrogen balance and act as fuel for rapidly dividing cells such as lymphocytes and enterocytes; maintaining immune responses and gut mucosal integrity

SECTION 11  Nutrition 1924 Gastrointestinal disease Nutrition support is required in gastrointestinal conditions that re- sult in impaired access to the gut, for instance as a result of proximal obstruction or dysmotility, or intestinal failure due to short bowel or mucosal disease. Liquid, oral, or enteral feeds may be used to induce remission in Crohn’s disease with equivalent efficacy to steroids. Patients with proximal enterocutaneous fistulae may have high fluid and nutrient losses from the fistula. Parenteral nutrition may be essential to provide nutritional and fluid intake and reduce effluent that may compromise wound healing. However, in patients with low output fistulae who are able to manage their fluid and nutrient re- quirements orally or enterally, there is no evidence to suggest that ‘gut rest’ and parenteral nutrition increase rates of fistula closure. In severe acute pancreatitis, nutrition requirements are increased by the systemic inflammatory response and there are theoretical concerns of stimulation of pancreatic secretion by enteral feeding. Enteral feeding is often limited by gastric stasis in severe cases and intrajejunal feeding is associated with lower complications than par- enteral nutrition in this setting. Perioperative nutrition Malnourished patients undergoing surgery experience up to three times as many complications and a fourfold increase in mortality compared to well-​nourished individuals. Patients may be starved for prolonged periods prior to surgery due to obstruction or after surgery as a result of ileus. Surgery should be delayed where feasible in severely malnourished patients to provide a minimum of 10 to 14 days of adequate perioperative nutrition. Starvation immediately prior to surgery results in increased in- sulin resistance and complications postoperatively, and the simple expedient of providing a 50 g carbohydrate load orally two hours prior to surgery can speed postoperative recovery. Early reintroduc- tion of oral feeding after routine abdominal surgery is feasible and results in more rapid rehabilitation than waiting for unreliable clin- ical signs of gastrointestinal function to return prior to feeding. Palliative care Terminal illness—​whether due to benign or malignant disease—​is frequently associated with poor nutritional status resulting from catabolic effects of the underlying disease and associated anor- exia. Limited observational evidence suggests that both length and quality of life can be maintained for a period of time in some such patients with good initial performance status by the appropriate use of nutrition support. Patients with intestinal obstruction due to slow growing malignancy may derive benefit from parenteral nutri- tion, particularly if associated with a venting gastrostomy to prevent vomiting. However, the use of artificial nutrition support in all such cases needs to be carefully considered to ensure that the benefits out- weigh the additional burdens of feeding and that valuable time is not wasted setting up artificial nutrition in hospital for minimal gain. Delivering a nutrition service The hospital nutrition support team A multiprofessional team comprising clinician, specialist nurse, dietitian, and pharmacist as its core members is required to provide the full range of nutrition support services. By appropriate use of nu- trition support, reducing catheter-​related complications, and moni- toring patients receiving parenteral nutrition, such teams have been shown to provide significant cost savings as well as providing high-​ quality clinical care. Cost-​effectiveness of nutrition support Public health and social care expenditure relating to malnutrition in 2011–​2012 in the United Kingdom was estimated at £19.6 billion, equivalent to 15% of the healthcare budget. Oral nutrition support has been demonstrated to reduce mortality by up to 24% in some hospital and community settings, and to reduce complications (odds ratio 0.29—​confidence intervals 0.18–​0.47) and lengths of hospital inpatients’ stay. Modelling suggests that appropriate nutrition sup- port is highly cost-​effective despite high initial outlays in nutrition screening and costs of supplements. Future developments An increased awareness of the critical importance of nutrition in clinical care is likely to improve the recognition of malnutrition and lead to the institution of appropriate preventive measures with sig- nificant benefits in all areas of clinical medicine. An unfortunate lack of adequately powered trials has limited the application of innovative nutritional interventions, including novel nutrient substrates, to modulate inflammatory responses or explore disease-​specific feeds (Table 11.7.6), hence there is much potential still to be unlocked in the field of therapeutic nutrition. FURTHER READING Andrews PJ, et al. (2011). Randomised trial of glutamine, selenium or both to supplement parenteral nutrition for critically ill patients. BMJ, 342, d1542. Bozzetti F, et al. (2002). Central venous catheter related complications in 447 patients on home parenteral nutrition; an analysis of over 100,000 catheter days. Clin Nutr, 21, 475–​85. Briet F, et al. (2004). Effect of feeding malnourished patients for 1 mo on mitochondrial complex 1 activity and nutritional assessment measurements. Am J Clin Nutr, 79, 787–​94. Campbell SE, et al. (2002). Assessment of nutritional status in hospital in-​patients. QJ Med, 95, 83–​7. Cano NJM, et al. (2009). ESPEN guidelines for adult parenteral nutri- tion. Clin Nutr, 28, 359–​479. Dibb M, Soop M, Teubner A, et al. (2017). Home parenteral nutrition: Three decades of experience from a single referral centre. Clin Nutr., 36(2), 570–76. Druml C, et al. (2016). ESPEN guideline on ethical aspects of artificial nutrition and hydration. Clin Nutr, 35, 545–​56. Elia M (1982). The effects of nitrogen and energy intake on the me- tabolism of normal, depleted and injured man. Considerations for practical nutrition support. Clin Nutr, 1, 173–​92. Elia M (2003). The MUST Report: Nutritional Screening of Adults: A Multidisciplinary Responsibility. Development and Use of the Malnutrition Universal Screening Tool (MUST) for Adults. A report by the malnutrition advisory group of the British Association for Parenteral and Enteral Nutrition. BAPEN, Redditch. https://​www. bapen.org.uk/​pdfs/​must/​must-​report.pdf

11.7  Artificial nutrition support 1925 Elia M, et al. (2015). The Cost of Malnutrition in England and Potential Cost Savings from Nutritional Interventions. https://​www.bapen.org. uk/​pdfs/​economic-​report-​full.pdf Gauderer MW, Ponsky JL (1981). A simplified technique for con- structing a tube feeding gastrostomy. Surg Gynecol Obstet, 152, 83–​5. Harvey SE, et al. (2014). Trial of the route of early nutritional support in critically ill adults. N Engl J Med, 371, 1673–​84. Hashimoto K, et  al. (2015). Recent advances in intestinal and multivisceral transplantation. Adv Surg, 49, 31–​63. Heyland DK (2000). Parenteral nutrition in the critically ill pa- tient: more harm than good? Proc Nutr Soc, 59, 457–​66. Jeejeebhoy KN (2012). Malnutrition, fatigue, frailty, vulnerability, sarcopenia and cachexia: overlap of clinical features. Curr Opin Clin Nutr Metab, 15, 213–​19. Kalm LM, Semba RD (2005). They starved so that others could be better fed: remembering Ancel Keys and the Minnesota experiment. J Nutr, 135, 1347–​52. Keys A (1946). Human starvation and its consequences. J Am Diet Assoc, 22, 582–​7. Lewis SJ, et al. (2001). Early enteral feeding versus ‘nil by mouth’ after gastrointestinal surgery:  systematic review and meta-​analysis of controlled trials. BMJ, 323, 773–​6. Ljungqvist O, et al. (2002). Modulation of post-​operative insulin re- sistance by pre-​operative carbohydrate loading. Proc Nutr Soc, 61, 329–​36. Maple JT, et al. (2005). Direct percutaneous endoscopic jejunostomy: outcomes in 307 consecutive attempts. Am J Gastroenterol, 100, 2681–​8. Matsumoto CS, Subramanian S, Fishbein TM (2018). Adult Intestinal Transplantation. Gastroenterol Clin North Am, 47(2), 341–54. Mayer K, et al. (2003). Parenteral nutrition with fish oil modulates cytokine response in patients with sepsis. Am J Respir Crit Care Med, 167, 1321–​8. McWhirter JP, Pennington CR (1994). Incidence and recognition of malnutrition in hospital. BMJ, 308, 945–​8. Planck L, et  al. (2008). Nocturnal nutrition supplementation im- proves total body protein status of patients with liver cirrhosis: a randomised 12 month trial. Hepatol, 48, 557–​66. Shaw JF, et al. (1987). Whole body protein kinetics in severely septic patients. Ann Surg, 205, 288–​94. Stratton R, Smith T, Gabe S (2018). Managing malnutrition to im- prove lives and save money. BAPEN October 2018. www.bapen. org.uk/pdfs/reports/mag/managing-malnutrition.pdfUm adist, ut idunt vit eaquas peruptate labore pa volorum im qui underfe

SECTION 12 Metabolic disorders Section editor: Timothy M. Cox 12.1 The inborn errors of metabolism:
General aspects  1929 Timothy M. Cox and Richard W.E. Watts 12.2 Protein-​dependent inborn errors of metabolism  1942 Georg F. Hoffmann and Stefan Kölker 12.3 Disorders of carbohydrate metabolism  1985 12.3.1 Glycogen storage diseases  1985 Robin H. Lachmann and Timothy M. Cox 12.3.2 Inborn errors of fructose metabolism  1993 Timothy M. Cox 12.3.3 Disorders of galactose, pentose, and
pyruvate metabolism  2003 Timothy M. Cox 12.4 Disorders of purine and pyrimidine metabolism  2015 Anthony M. Marinaki, Lynette D. Fairbanks,
and Richard W.E. Watts 12.5 The porphyrias  2032 Timothy M. Cox 12.6 Lipid disorders  2055 Jaimini Cegla and James Scott 12.7 Trace metal disorders  2098 12.7.1 Hereditary haemochromatosis  2098 William J.H. Griffiths and Timothy M. Cox 12.7.2 Inherited diseases of copper metabolism: Wilson’s disease and Menkes’ disease  2115 Michael L. Schilsky and Pramod K. Mistry 12.8 Lysosomal disease  2121 Patrick B. Deegan and Timothy M. Cox 12.9 Disorders of peroxisomal metabolism
in adults  2157 Anthony S. Wierzbicki 12.10 Hereditary disorders of oxalate metabolism: The primary hyperoxalurias  2174 Sonia Fargue, Dawn S. Milliner, and
Christopher J. Danpure 12.11 A physiological approach to acid–​base disorders: The roles of ion transport and
body fluid compartments  2182 Julian Seifter 12.12 The acute phase response, hereditary periodic fever syndromes, and amyloidosis  2199 12.12.1 The acute phase response and C-​reactive protein  2199 Mark B. Pepys 12.12.2 Hereditary periodic fever syndromes  2207 Helen J. Lachmann, Stefan Berg,
and Philip N. Hawkins 12.12.3 Amyloidosis  2218 Mark B. Pepys and Philip N. Hawkins 12.13 α1-​Antitrypsin deficiency and the serpinopathies  2235 David A. Lomas