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Metabolic complications associated with HIV and highly active Antiretroviral Therapy. Enrique Mendoza MD, MSc.

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Metabolic complications associated with HIV and highly active Antiretroviral Therapy

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Metabolic complications associated with hiv and highly active antiretroviral therapy

Metabolic complications

associated with HIV and highly

active Antiretroviral Therapy

Enrique Mendoza MD, MSc


Metabolic complications associated with hiv and highly active antiretroviral therapy

Before the mid-1990s, effective anti-HIV therapy was unavailable. Patient care focused on preventing and managing infectious and neoplastic complications related to profound HIV-associated immunosuppression.

Metabolic complications were also identified during this period.


Metabolic complications associated with hiv and highly active antiretroviral therapy

The AIDS wasting syndrome was the most common such complication.

This condition, which still occurs in untreated patients with advanced disease or patients unresponsive to current anti-HIV treatments, leads to progressive loss of fat-free mass.


Metabolic complications associated with hiv and highly active antiretroviral therapy

The etiology is multifactorial, including decreased caloric intake, gastrointestinal dysfunction and intermediary metabolism dysfunction.


Metabolic complications associated with hiv and highly active antiretroviral therapy

Dyslipidemia occurs in untreated patients and consists of low total cholesterol, LDL and HDL levels and increased triglyceride levels.

The pathogenesis involves altered inflammatory cytokine levels, decreased triglyceride clearance and inhibition of lipoprotein lipase.


Metabolic complications associated with hiv and highly active antiretroviral therapy

Glucose homeostasis was initially reported to be normal but recently insulin resistance has been noted in some untreated patients. Interestingly, there were several reports of advanced atherosclerosis occurring more frequently than expected in untreated patients.


Metabolic complications associated with hiv and highly active antiretroviral therapy

Following the introduction in the mid-1990s of combination anti-HIV therapy, known as highly

Soon after the widespread adoption of HAART, reports of particular body-shape changes appeared, often occurring in association with distinct metabolic abnormalities.


Metabolic complications associated with hiv and highly active antiretroviral therapy

The constellation of these seemingly unique complications became known by various terms, most commonly the lipodystrophy syndrome(s).

Such metabolic toxicities are important components in the management of HIV-mediated disease


Metabolic complications associated with hiv and highly active antiretroviral therapy

The clinical features can include peripheral lipoatrophy (the loss of subcutaneous fat, clinically apparent primarily in the face and buttocks, but which is in fact generalized), and central lipohypertrophy (manifesting mainly as increased abdominal girth, and less frequently as an enlarged dorso-cervical fat pad).


Metabolic complications associated with hiv and highly active antiretroviral therapy

Unilateral or bilateral breast enlargement (another manifestation of lipohypertrophy) may also occur infrequently in both men and women, and is due to increased glandular fatty tissue.

The increase in abdominal girth is caused by increased amounts of visceral adipose tissue (VAT).


Metabolic complications associated with hiv and highly active antiretroviral therapy

Some patients with lipodystrophy syndrome(s) can develop significant dyslipidemia, glucose homeostasis abnormalities, asymptomatic hyperlactatemia, and bone demineralization.


Metabolic complications associated with hiv and highly active antiretroviral therapy

Although the dyslipidemia and insulin resistance are more prevalent in patients with body-shape changes, they can occur in patients without clinically apparent fat-mass changes.


Metabolic complications associated with hiv and highly active antiretroviral therapy

Overall, the dyslipidemia is most frequently documented, and does not necessarily predict the presence of the other abnormalities.

It consists of a variable increase in total cholesterol and LDL levels, an often significant increase in triglyceride levels, and usually no further reduction in the already decreased HDL level.

Abnormalities in other lipoprotein fractions, as well as proinflammatory and procoagulant changes, have also been variably noted. Overall an atherogenic lipid profile commonly occurs.


Metabolic complications associated with hiv and highly active antiretroviral therapy

Overall, body-shape changes were initially reported in 20-80% of patients after 1-2 years of therapy on early protease-inhibitor-containing HAART regimens. They occur less often in patients on non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens.


Metabolic complications associated with hiv and highly active antiretroviral therapy

Protease inhibitors affect multiple metabolic pathways and are associated with the development of atherogenic dyslipidemia, insulin resistance and lipohypertrophy.

Short-course monotherapy with protease inhibitors in HIV-negative individuals increases total cholesterol and triglyceride levels within a few weeks of starting therapy.


Metabolic complications associated with hiv and highly active antiretroviral therapy

In HIV-seropositive patients, protease-inhibitor-based HAART also alters lipid levels within a few weeks of initiating treatment, in the absence of any clinically evident effects on body-shape changes.


Metabolic complications associated with hiv and highly active antiretroviral therapy

Insulin resistance occurs in about one-third of patients on certain protease-inhibitor-based regimens, although the concurrent use of thymidine NRTIs has also been associated with this abnormality.

Asymptomatic type 2 diabetes mellitus is diagnosed in 5-10% of patients.

Protease inhibitors block, in a hierarchical manner, the transport function of SLC2A4 previously termed glucose transporter type 4 [GLUT4] receptors involved in glucose uptake and lead to insulin resistance.


Metabolic complications associated with hiv and highly active antiretroviral therapy

New classes of anti-HIV drugs, such as inhibitors of virus entry or fusion, chemokine-receptor antagonists, and integrase inhibitors, have not yet been adequately studied for their potential to cause metabolic toxicity


Metabolic complications associated with hiv and highly active antiretroviral therapy

Clinical Sequelae

Altered body-fat distribution, dyslipidemia, and insulin resistance have important clinical sequelae.

The body-shape changes impair quality of life, with a negative impact on patients' adherence to drug treatment regimes.

Hypertriglyceridemia also increases the risk of pancreatitis, but the major clinical research focus has been on the increased risk of CVD.


Metabolic complications associated with hiv and highly active antiretroviral therapy

Management

Alterations to lifestyle factors that are amenable to change, such as existing cigarette smoking, limited physical activity, poor dietary habits, and control of hypertension, should be aggressively undertaken, whenever possible.

Type 2 diabetes mellitus, often asymptomatic when diagnosed, should be treated as per current guidelines.


Metabolic complications associated with hiv and highly active antiretroviral therapy

The management of dyslipidemia follows published National Cholesterol Education Program guidelines for HIV-negative individuals. Switching from a metabolically active protease-inhibitor-based HAART regimen to one with a metabolically less active protease inhibitor (ritonavir boosted atazanavir, or saquinavir), to an NNRTI, or to the NRTIs abacavir or tenofovir might decrease total cholesterol, LDL, and triglyceride levels.

Switching to an NNRTI-based regimen might increase HDL levels and reduce an elevated ratio of total cholesterol to HDL.


Metabolic complications associated with hiv and highly active antiretroviral therapy

Statins decrease elevated total cholesterol and LDL levels but their use is tempered by the pharmacokinetic interaction between protease inhibitors and statins.

As noted, protease inhibitors inhibit the cytochrome P450-3A4 metabolic pathway, which might lead to increased statin-associated toxic effects. Pravastatin, which is not metabolized by this system, is the safest statin to use.


Metabolic complications associated with hiv and highly active antiretroviral therapy

Atorvastatin can be used cautiously, but the safety of fluvastatin is uncertain. Simvastatin and lovastatin are contraindicated.

The safety and effectiveness of newer statins are under investigation.

Use of ezetimibe, a cholesterol uptake inhibitor, might be beneficial. Fibrates are indicated in patients with hypertriglyceridemia and low HDL levels.


Metabolic complications associated with hiv and highly active antiretroviral therapy

A study published in 2005 suggests that switching to a metabolically less active anti-HIV drug is less beneficial than using pharmacotherapy for dyslipidemia. The lipid-lowering effectiveness of standard pharmacotherapy is, however, often inadequate.

Dual statin and fibrate treatment might, therefore, be needed, which, although more effective, might be associated with greater toxicity.

Fish oils might be useful in the treatment of hypertriglyceridemia.


Metabolic complications associated with hiv and highly active antiretroviral therapy

There are no approved pharmacologic treatments for insulin resistance. Lifestyle interventions including dietary alterations, increasing exercise, decreasing caloric intake, and controlling hypertension are, however, useful in reversing this abnormality in HIV-negative patients and in avoiding the development of type 2 diabetes mellitus.


Metabolic complications associated with hiv and highly active antiretroviral therapy

Reports suggest that the insulin-sensitizing drug metformin can improve insulin resistance and possibly decrease lipohypertrophy although this approach is also unconfirmed. It is important to note that metformin can further decrease amounts of subcutaneous fat.

Avoiding the initial development of lipohypertrophy by using HAART regimens with metabolically more neutral components requires confirmation from ongoing clinical studies


Metabolic complications associated with hiv and highly active antiretroviral therapy

Signal – Transduction Pathways:

An Introduction to Information

Metabolism


Metabolic complications associated with hiv and highly active antiretroviral therapy

Volume 351:696-705 August 12, 2004Number 7

Case 25-2004 — A 49-Year-Old Woman with Severe Obesity, Diabetes, and Hypertension

Janey S. Pratt, M.D., Susan Cummings, M.S., R.D., Deborah A. Vineberg, Psy.D., Fiona Graeme-Cook, M.D., and Lee M. Kaplan, M.D., Ph.D.


Metabolic complications associated with hiv and highly active antiretroviral therapy

Presentation of Case

A 49-year-old woman was evaluated at this hospital for the managementof obesity. She had been overweight since childhood; at theage of 10 years she weighed 45.4 kg, at the age of 18 she weighed88.5 kg, and throughout most of her adult life she weighed between108.9 and 129.3 kg. She was able to lose weight on more than10 occasions with diet and exercise but always regained it withintwo to three years. Dexfenfluramine was prescribed for weightloss when she was 40 years old, and she lost 11.3 kg but gained22.6 kg after she stopped taking the drug.

Presentation of Case


Metabolic complications associated with hiv and highly active antiretroviral therapy

Ten years earlier, diabetes mellitus had been diagnosed; itwas controlled with metformin hydrochloride and glyburide. Twicewithin the 12 years before the evaluation, the woman had notedintermittent, sharp pain radiating down her left leg. Plainradiographs showed that there was narrowing of the disk spacesbetween the second and third and the third and fourth lumbarvertebrae and first-degree spondylolisthesis of the fifth lumbarvertebra. Despite several courses of physical therapy and theintermittent use of ibuprofen, intermittent pain persisted.


Metabolic complications associated with hiv and highly active antiretroviral therapy

An episode of exertional chest pain had occurred five yearsbefore the evaluation; radionuclide scanning of the heart revealeda large anterior defect suggestive of ischemia. Coronary-arteryangiography demonstrated 50 percent occlusion of one coronaryartery. Aspirin and pravastatin were prescribed.


Metabolic complications associated with hiv and highly active antiretroviral therapy

Three years earlier, treatment with insulin had been startedbecause of inadequate control of blood glucose. At the sametime, hypertension was diagnosed (blood pressure, 164/114 mmHg), and treatment with lisinopril was started. An ophthalmologistdiagnosed diabetic retinopathy. Two years earlier, the patienthad reported the sensation of burning on the soles of her feetthat awakened her at night. Gabapentin was prescribed. She hadexperienced episodes of depression intermittently for 11 years;they had been treated first with bupropion and for the past3 years with fluoxetine


Metabolic complications associated with hiv and highly active antiretroviral therapy

The patient (gravida 2, para 2) had delivered both her childrenby cesarean section and worked as a registered nurse for a healthcare agency. A tonsillectomy had been performed when she was14 years old. She was allergic to penicillin. She had been divorcedfor five years, and she lived with her two grown children. Shehad smoked 10 cigarettes per day for several years but had stoppedsmoking many years before her evaluation, she drank alcoholinfrequently.


Metabolic complications associated with hiv and highly active antiretroviral therapy

Her brother had undergone coronary-artery bypassgrafting when he was 41 years old, and her mother had died ofa myocardial infarction at the age of 52. Her parents and allthree of her brothers were obese. Her medications included insulin(55 U in the morning and 30 U in the evening), metformin, fluoxetine,atorvastatin, lisinopril, ibuprofen, conjugated estrogens, medroxyprogesteroneacetate, a calcium supplement, aspirin, and multivitamins.


Metabolic complications associated with hiv and highly active antiretroviral therapy

On physical examination, the patient's height was 155 cm andher weight 129.5 kg. The body-mass index (the weight in kilogramsdivided by the square of the height in meters) was 52. The bloodpressure was 156/93 mm Hg, the heart rate 104 beats per minute,and the respiratory rate 16 breaths per minute. Examinationof the lungs and heart revealed no abnormalities. The abdomenwas obese and nontender, with no organomegaly. She had moderatefolliculitis under a grade 2 abdominal pannus (i.e., the layerof fat covers the groin area in line with the upper-thigh crease).


Metabolic complications associated with hiv and highly active antiretroviral therapy

The distal pulses were palpable, and there was no peripheraledema. There were no focal neurologic deficits. Electrolytelevels, the results of liver-function tests, and the white-celland platelet counts were normal. The results of other laboratorytests are shown in Table 1.


Metabolic complications associated with hiv and highly active antiretroviral therapy

Discussion of Management

Dr. Janey S. Pratt: Obesity is epidemic. More than 65 millionAmericans, or 1 in 3, have obesity (defined as a body-mass indexgreater than 30), and more than 10 million have severe obesity(a body-mass index greater than 40).1,2 This patient, who hada body-mass index of 52, had severe, lifelong obesity, whichwas complicated by type 2 diabetes mellitus, hyperlipidemia,hypertension, depression, and low-back pain. She has been unableto sustain weight loss with the use of a variety of diets andmedication. She was referred to us to explore surgical managementof her obesity. Since obesity is a multifactorial, chronic disease,its treatment requires a multidisciplinary, long-term approach.Members of this patient's multidisciplinary clinical team willdiscuss aspects of her assessment and care.


Metabolic complications associated with hiv and highly active antiretroviral therapy

Medical Evaluation

Dr. Lee M. Kaplan: The medical evaluation of this patient withobesity was focused on identification of the causes and complicationsof the excess weight and on treatment to reverse them or preventtheir progression. Therapeutic decisions in a case such as thisone are guided by the degree of obesity and the severity ofthe medical and psychological complications. For the majorityof persons with obesity, a specific cause cannot be identified.2


Metabolic complications associated with hiv and highly active antiretroviral therapy

Even when endocrine disorders such as hypothyroidism or Cushing'sdisease are present, they are rarely the cause of the obesity.In an increasing number of patients, the onset or exacerbationof obesity correlates with the use of medications that causeweight gain as a side effect. When I first saw this patient,she was taking insulin, which is commonly associated with weightgain, and fluoxetine, which causes weight gain in a minorityof patients. However, she had been severely overweight sincelate childhood, before those medications were administered.


Metabolic complications associated with hiv and highly active antiretroviral therapy

The common disorders associated with obesity can be dividedinto five major categories: metabolic, structural, degenerative,neoplastic, and psychological (Table 2).2 Several of them (obstructivesleep apnea, thromboembolism, and degenerative arthritis) resultfrom both structural and metabolic dysfunction. The relationshipof each complication to the body-mass index varies widely, withthe risk of diabetes and other metabolic complications increasingat a body-mass index as low as 23 to 25 and the risk of anatomicalcomplications increasing most strikingly in persons with severeobesity. Among the many complications of obesity, obstructivesleep apnea, fatty-liver disease, gastroesophageal reflux disease,fungal skin infections, and nutrient deficiencies are the mostcommonly undiagnosed or undertreated complications in patientspresenting for care at a specialized obesity center.2


Metabolic complications associated with hiv and highly active antiretroviral therapy

This patienthad diabetes, hypertension, and hyperlipidemia. As part of theinitial evaluation, a sleep study was conducted, which showedthat she had sleep apnea. Although it was not among the symptomsshe initially described, she later reported that she had snoredand had had difficulty sleeping for many years.


Metabolic complications associated with hiv and highly active antiretroviral therapy

People with obesity have an elevated risk of all the diseasesfor which patients are most commonly screened: hypertension,hyperlipidemia, diabetes mellitus, and cervical, breast, prostate,and colorectal cancers. Ironically, however, several studieshave shown that they are less likely to undergo screening forthese disorders than are people of normal weight.1,2 In thispatient, screening was complete and up to date. The strongestmedical contraindications for weight-reduction surgery are severelung disease, unstable cardiovascular disease, uncontrolledclotting disorders, portal hypertension with gastric varices,pregnancy, and ongoing substance abuse. This patient had noneof these disorders.


Metabolic complications associated with hiv and highly active antiretroviral therapy

Nutritional Evaluation

Susan Cummings: This patient's comprehensive nutrition evaluationincluded the assessment of anthropometric data and social, nutritional,and behavioral factors. Our objectives were to assess her riskfor complications of obesity, to identify factors contributingto her obesity, if possible, and to provide baseline data toassess the outcomes of treatment.


Metabolic complications associated with hiv and highly active antiretroviral therapy

The measurements of height, weight, and waist circumferenceprovide an indication of a patient's risk for complicationsof obesity (Table 3).1,2 Calculations based on the patient'sheight, weight, and age are used to estimate energy expenditure(Table 4).3 This patient's weight put her at extremely highrisk for complications. Her energy needs were estimated to be2500 kcal per day to maintain her current weight, but her reportedintake was approximately 3000 kcal a day — 500 kcal morethan her net energy needs.


Metabolic complications associated with hiv and highly active antiretroviral therapy

The patient's weight history and that of her family may givesome indication of a genetic predisposition. In this patient,the weight history revealed that the onset of obesity was inlate childhood and that her highest weight as an adult was 129.3kg, the weight at the time of her presentation to us. Her lowestadult weight was 79.4 kg, immediately after dieting. Her dietinghistory included four commercial programs and many self-directeddiets. She had lost as much as 38.5 kg at one time through dieting,but like many people she always regained more weight than shehad lost from each diet, and she had gained more than 45.4 kgoverall during adulthood. Her family history revealed obesityin both parents and three brothers.


Metabolic complications associated with hiv and highly active antiretroviral therapy

The nutrition evaluation included a 24-hour recall of totalfood intake and the frequency of food intake, as well as inquiryinto hunger, satiety (how frequently she experienced hungerand what made her feel satiated), and behaviors such as bingeeating, grazing (eating not related to hunger), nighttime eating,eating in restaurants, and alcohol consumption. This informationhelped to determine the patient's usual food intake and providedan indication of the environmental influences on her eatingpatterns. Most of her calories were consumed at meals with largeportions of calorically dense foods. She ate three meals a daybut occasionally skipped lunch and had a planned snack in themidafternoon. She often ate in fast-food restaurants.


Metabolic complications associated with hiv and highly active antiretroviral therapy

The assessment of physical activity included information aboutthe activities of daily living, physical limitations, and structuredexercise. This patient was sedentary and did not engage in astructured program of exercise because of her chronic back pain.The patient's expectations concerning ideal weight were alsoaddressed, as were her self-efficacy (confidence in the abilityto make the necessary behavioral changes), motivation, readinessfor weight loss, and potential barriers to treatment. This patient'sprimary motivation to lose weight was to improve her overallhealth and well-being.


Metabolic complications associated with hiv and highly active antiretroviral therapy

Psychological Evaluation

Dr. Deborah A. Vineberg: Psychological assessment of patientswith obesity was once thought to be important in identifyingthe cause of the obesity, which was believed to be related toa lack of self-control or to a psychological addiction to food.The current understanding is that the most important reasonsfor this evaluation are to diagnose and treat psychologicaldisorders that result from the obesity, compound the existingweight problem, or interfere with effective treatment.


Metabolic complications associated with hiv and highly active antiretroviral therapy

Pretreatmentevaluation of this patient included screening for psychiatricdisorders that could interfere with the management of obesity.Axis I disorders in the Diagnostic and Statistical Manual ofMental Disorders, fourth edition (psychiatric disorders thatare clinical in nature,4 such as depression or anxiety) andeating disorders (such as binge eating or bulimia) can complicatemedical management unless they are treated adequately.


Metabolic complications associated with hiv and highly active antiretroviral therapy

Thispatient reported poor self-esteem and a profound sense of inferioritythat she attributed to being overweight. She reported that stressfulevents, including the births of her children and her divorce,had exacerbated her weight problem. At the time of her evaluationshe identified her job, single parenthood, and her declininghealth as stressful factors in her life. At the initial evaluationher Beck Depression Inventory5 score was 19, which correspondsto mild-to-moderate depression. Obesity is strongly associatedwith depression.


Metabolic complications associated with hiv and highly active antiretroviral therapy

Persons over 50 years of age who are obeseare twice as likely to become depressed within five years asthose who are not obese,6 but when followed for five years,those who are depressed are not at increased risk of becomingobese. Thus, obesity is a risk factor for depression, but theconverse is not true.


Metabolic complications associated with hiv and highly active antiretroviral therapy

Psychological complications associated with gastric bypass aresimilar to those associated with other major surgical procedures;transient postoperative depression is the most frequent complication.Exacerbation of preexisting psychiatric anxiety or depressionis rare, and more than 90 percent of cases of depression and50 percent of cases of anxiety disorders improve.7 Depressionbefore weight-loss surgery does not worsen outcomes8; in fact,one study found that patients with higher Beck Depression Inventoryscores lost more weight after surgery than those with lowerscores.9


Metabolic complications associated with hiv and highly active antiretroviral therapy

This patient described neither binge eating nor inappropriatebehaviors such as self-induced vomiting or the use of laxativesor diuretics. She demonstrated good insight into the psychologicalfunction of her weight, which she characterized as providingher with a sense of safety and a form of protection. She admittedto being fearful of substantial weight change, and she worriedabout her potential for self-sabotaging behavior. She was providedadditional sessions with a psychologist to address these concerns.


Metabolic complications associated with hiv and highly active antiretroviral therapy

The presence of an Axis II disorder (a personality disorderor mental retardation) can lead to difficulties in managementor can be a contraindication to surgery and should be addressedbefore surgery is undertaken. This patient did not have an AxisII disorder, and she had no family history of psychiatric disorders.Thus, she did not have psychiatric contraindications to surgery.


Metabolic complications associated with hiv and highly active antiretroviral therapy

We also discussed her personal support system, since the involvementof family or friends in medical and surgical treatment of obesitycan improve the outcome.10 She reported that both her familyand her friends were supportive of her efforts to lose weight.


Metabolic complications associated with hiv and highly active antiretroviral therapy

Weight-Loss Surgery

Dr. Pratt: A clinical-team meeting of the obesity-medicine specialist,nutritionist, and psychologist concluded that this patient wasa suitable candidate for bariatric, or weight-loss, surgery.The term bariatric comes from the Greek word "baros," meaning"weight," and refers to the treatment of weight disorders. Manydifferent surgical procedures have been tried during the past50 years, but there are three major categories in current use:restrictive operations (gastroplasties with the use of adjustablegastric bands), malabsorptive operations (biliopancreatic diversions),and gastric bypasses.


Metabolic complications associated with hiv and highly active antiretroviral therapy

Each can be performed either laparoscopicallyor in an open fashion. The standard types of gastric bypassdo not carry the risk of clinically significant protein malnutritionthat is associated with biliopancreatic-diversion procedures.


Metabolic complications associated with hiv and highly active antiretroviral therapy

Weight-loss surgery provides the best long-term results forpatients with moderate (class II) or severe (class III) obesitywho have not responded to more conservative approaches.11,12It is generally reserved for patients with a body-mass indexgreater than 40 or for those with a body-mass index greaterthan 35 whose obesity is complicated by one or more major diseases.This patient met the criteria for this approach, since she hada body-mass index of 52 and several major complications andwas unable to maintain weight loss by other means.


Metabolic complications associated with hiv and highly active antiretroviral therapy

The overall morbidity and mortality associated with gastricbypass surgery are approximately 10 percent and less than 1percent, respectively.13,14 Early postoperative complicationsof laparoscopic gastric bypass surgery include wound infections(incidence, 3 percent), anastomotic leak (2 percent), bowelobstruction (2 percent), gastrointestinal hemorrhage (2 percent),and pulmonary embolus (less than 0.5 percent). Late complicationsinclude bowel obstruction (3 percent) and stomal stenosis (5percent)13; both of these problems are more common after laparoscopicprocedures than after open procedures.


Metabolic complications associated with hiv and highly active antiretroviral therapy

Although reported inless than 1 percent of cases,7 anastomotic ulcers have beenone of the most common late postoperative complications in myexperience. In patients who have gastric bypass surgery, thereis often improvement or resolution of coexisting diseases suchas diabetes,15 hypertension, hyperlipidemia, and sleep apnea,12as well as improved quality of life.7,14 For this patient, mycolleagues and I believed that the risks of continued obesityoutweighed those of bariatric surgery and its potential complications.


Metabolic complications associated with hiv and highly active antiretroviral therapy

Laparoscopic Roux-en-Y gastric bypass was recommended, becausethis procedure is associated with the best long-term outcomes.14,16This operation includes a restrictive procedure and a short-limbgastroduodenal bypass (Figure 1). It does not result in protein-caloriemalabsorption, but it appears to induce neurohumoral effectsthat result in decreased hunger, accelerated postprandial satiety,and diminished emotion-based or reward-based eating.2 The physiologicaland molecular mechanisms of these effects remain poorly understood.


Metabolic complications associated with hiv and highly active antiretroviral therapy

In the current case, preparation for surgery involved the fullmultidisciplinary team. The preoperative nutrition program includedan individual session of nutrition counseling with a dietitianand a group education session to familiarize the patient withthe postoperative diet protocol. The diet to be followed aftergastric bypass surgery is advanced in a staged approach (Table 5).Psychological counseling was instituted to assist the patientin making the behavioral changes that would be required aftersurgery.


Metabolic complications associated with hiv and highly active antiretroviral therapy

The preoperative medical evaluation included a thoroughassessment of the operative risks and the need for perioperativemanagement of coexisting diseases, with discussion among theobesity-medicine physician, anesthesiologist, and surgeon tooptimize her care.


Metabolic complications associated with hiv and highly active antiretroviral therapy

The operation took about three hours. The surgical team firstgained access by placing two 12-mm ports and three 5-mm portsthrough the abdominal wall in the upper abdomen — onefor a camera, one for the liver retractor, one for staplingdevices, and the other two for graspers to manipulate the stomachand intestines. The stomach was first divided by staplers acrossthe cardia, creating a 30-ml proximal gastric pouch (Video Clip1 in the Supplementary Appendix, available with the full textof this article at www.nejm.org). We then created a 100-cm Rouxlimb by dividing the intestines, stapling a jejunojejunostomy(Video Clip 2 in the Supplementary Appendix), and passing thelimb behind the colon and stomach (Video Clip 3 in the Supplementary Appendix).


Metabolic complications associated with hiv and highly active antiretroviral therapy

Finally, this limb was stitched to the pouch in adouble-layer anastomosis 1.5 cm in diameter (Video Clip 4 inthe Supplementary Appendix). Because the liver appeared fatty,a wedge-biopsy specimen of the liver was obtained. Postoperatively,an amidotrizoic acid (Gastrografin) swallow examination confirmedthat the gastrojejunal anastomosis was intact and without leak.The patient was discharged on the third hospital day while followinga stage 1 diet (Table 5).


Metabolic complications associated with hiv and highly active antiretroviral therapy

Pathological Discussion

Dr. Fiona Graeme-Cook: The specimen obtained by liver biopsyrevealed hepatocellular steatosis with a very few foci of ballooningdegeneration; the portal tracts showed slight proliferationof the bile ductules with minimal chronic inflammatory infiltrate(Figure 2A). Glycogenated hepatocellular nuclei were scattered.These findings are consistent with the presence of nonalcoholicfatty liver disease, without evidence of steatohepatitis, fibrosis,or cirrhosis.


Metabolic complications associated with hiv and highly active antiretroviral therapy

In the presence of insulin resistance, high levels of circulatinginsulin lead to high levels of free fatty acids within the liver,increasing the synthesis of triglycerides. Although the mechanismis not completely understood, hepatocytes accumulate fat, manifestedas hepatocellular steatosis. This is the most common findingin the liver in patients with severe obesity, present in morethan 75 percent of cases.


Metabolic complications associated with hiv and highly active antiretroviral therapy

The additional feature of glycogenatednuclei is also a marker for insulin resistance and hyperglycemia.Steatohepatitis may complicate steatosis, possibly as a resultof excessive -oxidation of fatty acids by hepatocellular mitochondria.The resultant oxidative stress is thought to lead to peroxidationof lipids, resulting in hepatocyte necrosis, an influx of mononuclearinflammatory cells, and eventually, fibrosis and cirrhosis (Figure 2B). 17,18


Metabolic complications associated with hiv and highly active antiretroviral therapy

Discussion of Outcome

Dr. Kaplan: During the early postoperative period, the patient'smost prominent symptom was constipation, which was probablya result of mild dehydration. The mobilization of stored fatby lipolysis consumes prodigious amounts of water, and fluidrequirements are high during the first several months aftersurgery. During the first few weeks, patients are closely monitoredfor dehydration, which may be manifested as constipation, lethargy,or light-headedness. The use of diuretics or other antihypertensiveagents often must be reduced or stopped altogether in the immediatepostoperative period.


Metabolic complications associated with hiv and highly active antiretroviral therapy

This patient's blood pressure remainednormal, and the lisinopril was discontinued without adverseeffect. Her blood sugar levels became normal within two daysafter surgery, despite the discontinuation of insulin and metformin.This rapid improvement in insulin sensitivity within severaldays after surgery is typical, and many patients require littleor no therapy for their diabetes during this time. To avertpotentially life-threatening hypoglycemic episodes, her bloodglucose levels were monitored frequently and insulin and sulfonylureaswere avoided.


Metabolic complications associated with hiv and highly active antiretroviral therapy

Ten days after surgery, she had lost 9.1 kg. Three months afterthe operation, she was eating three meals and two snacks dailyand had lost 27.2 kg. Six months after surgery, she had lost37.2 kg and was eating most foods without having symptoms. Participationin postoperative programs of nutrition education and cognitivebehavioral therapy appears to minimize both short-term complicationsrelated to nutritional issues and subsequent weight gain.10,11


Metabolic complications associated with hiv and highly active antiretroviral therapy

Beginning six months after surgery, the patient participatedin a monthly program for surgical support and education, whichprovides ongoing support and counseling. Her weight decreasedby 54.4 kg, to 70.3 kg, during the first 12 months after surgery.Excess skin with ptosis in the lower abdomen was treated withabdominoplasty 15 months after the weight-loss surgery. Shelater regained approximately 4.5 kg, and her weight then stabilizedat 74.8 kg for the next year.


Metabolic complications associated with hiv and highly active antiretroviral therapy

Nutritional Outcome

Two years after surgery, the patient's body-mass index was 30,down from 52, and her energy expenditure was estimated to beabout 1800 kcal per day, down from 2500 kcal per day. She atethree meals a day and did not routinely eat snacks. She experiencedsatiety with half-normal portions of food, and her hunger returnedabout five hours after each meal. She tolerated all types offood, although she avoided concentrated carbohydrates at thebeginning of each meal as a way of preventing the dumping syndrome(i.e., rapid gastric emptying). She did not have any changein her food preferences. She walked 4.8 km a day and reportedenjoying exercise for the first time.


Metabolic complications associated with hiv and highly active antiretroviral therapy

Medical Outcome

Two years after surgery, the patient's diabetes improved butdid not completely resolve. She no longer required insulin,and her metformin dose decreased from 850 mg taken three timesdaily to 500 mg taken twice daily. Her levels of hemoglobinA1c and urinary microalbumin fell (Table 1). Her diabetic retinopathydid not progress. Her sleep apnea, hypertension, and folliculitisresolved. Her lumbar back pain and sciatica improved substantially.Her hyperlipidemia remained well controlled with the use ofa lower dose of atorvastatin than she was taking before thesurgery, and there was no progression of her coronary arterydisease.


Metabolic complications associated with hiv and highly active antiretroviral therapy

A deficiency of micronutrients is common after gastric bypasssurgery. We regularly assessed the patient's levels of iron,calcium, vitamin B12, vitamin D, and vitamin K. Iron deficiencydeveloped approximately 10 months after surgery (Table 1). Itwas treated successfully with oral ferrous bisglycinate andpolysaccharide iron supplementation. Before surgery, she hadbeen found to have a vitamin B12 deficiency, which occurs ina small number of patients with obesity who have followed manydiet programs. Intranasal vitamin B12 supplementation was begunbefore the operation and was continued afterward, and two yearslater she had normal levels of vitamin B12 (Table 1).


Metabolic complications associated with hiv and highly active antiretroviral therapy

Secondaryhyperparathyroidism from malabsorption of calcium and vitaminD occurs in more than 60 percent of patients after gastric bypass.Metabolic bone disease is common and must be screened for andtreated. This patient took prophylactic supplementation withan oral calcium preparation (1000 mg of elemental calcium perday), and her levels of calcium, vitamin D, and parathyroidhormone have remained normal.


Metabolic complications associated with hiv and highly active antiretroviral therapy

Psychological Outcome

Six weeks after the operation, the patient recognized feelingsof loss related to being unable to overindulge in food. Shecommented, "You fixed my stomach, but I need to fix my head,"alluding to the need to focus on psychological triggers foreating that could no longer be satisfied by food. Twelve weeksafter surgery, she reported feeling "great." She was excitedabout her increased energy, and the Beck Depression Inventoryscore fell to 3, within the range of minimal depressive symptoms,and it remained at that level thereafter. She stopped takingfluoxetine.


Metabolic complications associated with hiv and highly active antiretroviral therapy

Two and a half years after the gastric bypass surgery, bothher self-confidence and her self-esteem have increased. Sheis more assertive in her relationships, with positive results.


Metabolic complications associated with hiv and highly active antiretroviral therapy

Dr. Pratt: This case illustrates the importance of a multidisciplinaryteam that includes an obesity-medicine specialist, a nutritionist,a psychologist, and a surgeon to ensure optimal medical andpsychological results from weight-loss surgery.1,10,19 Althoughthis patient was able to initiate exercise on her own, it isimportant to include a physical therapist or trainer when needed.Although her obesity was not cured, since her body-mass indexremained elevated (at 30), the team viewed this case as havinga successful outcome.


Metabolic complications associated with hiv and highly active antiretroviral therapy

Dr. A. Benedict Cosimi (Surgery): How would you assess whetherthe patient's psychological issues were solved or complicatedby the surgery? This patient considered her weight a protectiveshield. How did she feel when this shield disappeared?


Metabolic complications associated with hiv and highly active antiretroviral therapy

Dr. Vineberg: Instead of using the weight as a protection, sheworked to establish appropriate boundaries with people in herlife, so that she could maintain appropriate emotional distancethat did not depend on the physical or emotional distance causedby her size.


Metabolic complications associated with hiv and highly active antiretroviral therapy

Dr. Kaplan: It is not clear whether the protection that shefelt the excess weight provided was a primary or a secondaryevent. If you are shunned in society because of obesity, youmay then use the weight as an excuse not to interact with people.


Metabolic complications associated with hiv and highly active antiretroviral therapy

Dr. Carlos Fernández-del Castillo (Surgery): The adjustablegastric band has been approved by the Food and Drug Administrationfor use in the United States. I anticipate that its applicationis an easier operation than bypass. Why was it not used here?


Metabolic complications associated with hiv and highly active antiretroviral therapy

Dr. Pratt: The early experience with the adjustable gastricband in the United States showed a high rate of reoperation,20and definitive studies of long-term outcomes are not yet available.To achieve an optimal outcome, the band has to be adjusted everytwo to six months by the addition or removal of saline. Thisdependence on frequent follow-up visits suggests that successwith this procedure may be more dependent on voluntary behaviorthan the success observed after gastric bypass.


Metabolic complications associated with hiv and highly active antiretroviral therapy

Dr. Jay Vacanti (Pediatric Surgery): Can you comment on theuse of surgery in the management of pediatric obesity?


Metabolic complications associated with hiv and highly active antiretroviral therapy

Dr. Pratt: Obesity in adolescents is being treated surgicallyin several centers around the country, including the WeightCenter.21 Although the pediatric program here focuses primarilyon behavioral and medical approaches, gastric bypass surgeryhas been used to treat a few teenagers with severe obesity andobesity with medical complications, such as type 2 diabetesmellitus or obstructive sleep apnea, who have not been responsiveto other interventions. Recent studies have shown that resolutionof diabetes is most likely in patients who have had it for lessthan five years, so waiting to perform surgery in children withtype 2 diabetes may be more dangerous in the long term thanperforming the surgery.22


Metabolic complications associated with hiv and highly active antiretroviral therapy

Gracias


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