Endgames Case Review

Unexpected rapid weight gain in a patient with HIV and anorexia

BMJ 2015; 351 doi: https://doi.org/10.1136/bmj.h5551 (Published 29 October 2015) Cite this as: BMJ 2015;351:h5551
  1. Malika Mohabeer Hart, specialist registrar1,
  2. Marta Boffito, consultant physician in HIV medicine1,
  3. Anton Pozniak, consultant physician in HIV medicine1
  1. 1Department of HIV and Sexual Health, Chelsea and Westminster Hospital NHS Foundation, London SW10 9NH, UK
  1. Correspondence to: M Mohabeer Hart malikamohabeer{at}gmail.com

A 45 year old man presented to outpatients in January 2015 with unexplained weight gain and shortness of breath. He was HIV positive (diagnosed in the early 1990s) and was on combination antiretroviral therapy (tenofovir, emtricitabine, and darunavir boosted with ritonavir). His HIV infection was well controlled with an undetectable HIV viral load and a CD4 count of 497×106/L.

His medical history was complex, including depression, schizophrenia, anorexia, and epilepsy. He had been treated for adenocarcinoma of the lung and also had osteoporosis and hypertriglyceridaemia. He was therefore taking many drugs including pregabalin, omeprazole, gabapentin, clonazepam, lithium carbonate, loperamide, metoclopramide, zopiclone, and fenofibrate.

In October 2013 he was prescribed megestrol for anorexia and low body weight (64 kg), but this was stopped in May 2014 after he gained weight. Five months later, he gained another 10 kg and his blood pressure rose from 130/83 mm Hg to 163/97 mm Hg. He was breathless and developed a chronic cough in November 2014. Blood tests showed a rise in alanine aminotransferase from 65 IU/L (reference value <40) in August 2014 to 129 IU/L in November 2014.

In January 2015 he reported further weight gain (to 91 kg) and breathlessness. His abdominal girth had increased and he had developed purple abdominal striae (figure). He had no intra-abdominal accumulation of fluid (confirmed by ultrasonography). His face was moon shaped. His morning serum cortisol was 32 nmol/L (130-690). On questioning he admitted that he used his partner’s fluticasone containing inhaler to alleviate his breathlessness.

Questions

  • 1. What is the most likely diagnosis?

  • 2. How would you manage this patient?

  • 3. What is the take home message for doctors working in primary care?

Answers

1. What is the most likely diagnosis?

Short answer

Cushing’s syndrome due to excess exposure to corticosteroid drugs.

Discussion

The symptoms and signs of Cushing’s syndrome include acne, weight gain with centripetal obesity, hypertension, hirsuitism, diabetes, easy bruising, violaceous striae (which in general practice are usually seen in overweight, rapidly growing adolescents rather than as part of Cushing’s syndrome), mood swings, increased susceptibility to infections, low libido, osteoporosis, and menstrual irregularities. Symptoms develop gradually and insidiously and diagnosis may therefore be delayed.

The most common cause of Cushing’s syndrome is excess intake of corticosteroids—high doses or prolonged or frequent courses.1 Artificial corticosteroids act in a similar way to steroid hormones produced by the body. They are used for their potent anti-inflammatory and immunosuppressive effects and are available as tablets, inhalers, topical agents, and injections. They are useful in the treatment of a wide range of conditions, including inflammatory bowel disease, joint and connective tissue diseases, autoimmune diseases, allergies, and asthma. They are also used to correct an endogenous deficiency of steroids (Addison’s disease) and in the treatment of some cancers.

Short courses of steroids rarely cause serious adverse effects. However, it is important to consider their potential complications when prescribing them long term because adverse effects are more likely when they are taken for prolonged periods, as repeated courses, or at high doses.

Drug-drug interactions are an increasingly important, and sometimes unrecognised, cause of prolonged excess exogenous exposure to steroids. In such cases, the steroid is often prescribed at doses that would not normally cause serious complications, so the clinician will not be expecting these complications, especially if the drug is an inhaled or topical steroid, which are largely considered to be safe. Most steroids are metabolised by the cytochrome P450 (CYP450) group of enzymes, so drugs that inhibit these enzymes will boost circulating concentrations of steroids, which can lead to Cushing’s syndrome. This is relevant for HIV positive patients because combination antiretroviral therapy often includes potent CYP450 inhibitors, such as ritonavir and a new boosting agent called cobicistat.2 3 A quarter to a third of patients taking antiretroviral agents HIV treatment are at risk of serious drug-drug interactions.4

Endogenous Cushing’s syndrome affects just five in one million people each year and it is more common in women than in men. It is most often caused by a benign pituitary tumour that secretes adrenocorticotrophin. Other causes are adrenal hyperplasia, adenoma, or carcinoma and ectopic adrenocorticotrophin secretion by benign or malignant tumours (neuroendocrine tumours, thoracic carcinoma, or bronchogenic carcinoma).

2. How would you manage this patient?

Short answer

Stop exposure to excess steroids by switching to an alternative corticosteroid and monitor for complications of adrenal suppression.

Discussion

Patients with HIV who are on ritonavir containing antiretroviral therapy can develop iatrogenic Cushing’s syndrome and adrenal insufficiency as a result of its interaction with inhaled or intranasal glucocorticoids.5 Ritonavir is a potent inhibitor of the CYP450 3A4 isozyme, which metabolises certain steroids, including budesonide, fluticasone, mometasone, and triamcinolone.6

Fluticasone undergoes extensive first pass and systemic metabolism by CYP450 3A4, so inhibition of this enzyme can increase systemic concentrations of this drug. Coadministration of fluticasone propionate nasal spray (200 µg once daily) with ritonavir (100 mg orally twice a day) for seven days results in about a 25-fold increase in fluticasone peak plasma concentrations and a 350-fold increase in systemic exposure, which is associated with a marked reduction in plasma cortisol.7

The new booster agent cobicistat is also an inhibitor of CYP450 3A4 and similar interactions and precautions apply. The use of cobicistat is becoming more common—it is a component of a combination single tablet called Stribild and is also used to boost protease inhibitors. There is some evidence that inhaled or intranasal beclometasone is a relatively safe option in patients receiving protease inhibitors or cobicistat.8

In this case, it was not necessary to alter the antiretroviral therapy to prevent the interaction. However, when longer acting steroids are used, such as intra-articular or epidural triamcinolone injections,6 9 it may been necessary to remove the ongoing interaction by switching from ritonavir to a different antiretroviral therapy regimen. This requires expert input to ensure that the new antiretroviral regimen is safe and effective, and liaison with the patient’s HIV clinician is recommended.

3. What is the take home message for doctors working in primary care?

Short answer

Patients on long term drug treatment sometimes share drugs with other people. Doctors must be aware of drug-drug interactions when prescribing, but this case shows that the interacting drug is not always evident.

Discussion

It is well known, although not well publicised, that patients on long term drug treatment sometimes share drugs with other people. The risk factors for this phenomenon are the presence of multiple chronic comorbidities and polypharmacy.10

There are anecdotal accounts of patients with HIV sharing prescribed drugs with partners or friends, perhaps when they run out of their own antiretrovirals (if they are on the same regimen) or to save them from having to go to the outpatient department or general practitioner.

Although patients are always counselled about the proper use of prescribed and over-the-counter drugs before starting HIV therapy, these health messages can be forgotten. There is room for ongoing education to ensure patients are aware of the drug-drug interactions that are relevant to them and to remind patients to supply a full drugs history at every clinical encounter.

Doctors must be aware of drug-drug interactions while prescribing, and it is essential to take a detailed history of all the substances that the patient uses, not just those prescribed. If in doubt, specialist pharmacists are available to discuss cases of complex drug-drug interactions.

The University of Liverpool’s HIV drug interactions website (www.hiv-druginteractions.org) is a useful resource for checking potential drug-drug interactions that are relevant to combination antiretroviral therapy.

Patient outcome

The patient was advised to stop fluticasone and he was counselled about the misuse of drugs and the potential complications of drug-drug interactions. Given his ongoing respiratory symptoms, he was switched to a beclometasone containing inhaler. He was advised to ask his GP to evaluate the need for continued use of an inhaler and investigate for possible asthma.

At review in March 2015, he reported considerable weight loss and a decrease in abdominal girth. His cortisol had risen to 164 nmol/L, alanine aminotransferase had fallen to 62 IU/L, his weight was 81 kg, and his blood pressure was within the normal range, at 130/90 mm Hg.

Notes

Cite this as: BMJ 2015;351:h5551

Footnotes

  • Competing interests: We have read and understood BMJ policy on declaration of interests and declare the following interests: MB and AP have been paid advisers and/or received research grants from MSD, Gilead, BMS, Janssen, Viiv, Teva, Cipla, and Mylan; they are also unpaid members of the British HIV Association and European AIDS Clinical Society (AP only) guidelines group for HIV antiretroviral therapy. The authors have not been directed in any way by the above groups with regards to this article.

  • Provenance and peer review: Not commissioned; externally peer reviewed.

  • Patient consent obtained.

References

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