Multiple micronutrient deficiencies as a long-term complication of bariatric surgery

Abstract

Micronutrient deficiencies may develop as a long-term complication of bariatric surgery due to alteration of gut anatomy and disruption of normal gut absorption. Inadequate repletion of essential vitamin and mineral deficiencies can lead to multisystem dysfunction. We present a case of a woman in her 50s, with a history of Roux-en-Y gastric bypass over 10 years ago, who presented with generalised weakness and a diffuse desquamating rash. A punch biopsy performed was compatible with nutritional deficiency. Labs revealed low levels of micronutrients A, B₁, B₆, C, E, zinc and copper. The patient received intravenous micronutrients and an oral regimen, which improved her symptoms. Unfortunately, the patient died from cardiac arrest secondary to pulmonary oedema. This report highlights the importance of high suspicion of micronutrient deficiency in patients with a history of bariatric surgery and maintaining lifelong nutritional follow-up.

Background

Obesity is steadily on the rise among the US adult population, likely reaching 51% of the adult population by 2030.¹ Bariatric surgery is effective in treating morbidly obese patients and improves obesity-associated comorbidities. Common procedures include gastric bypass, sleeve gastrectomy and biliopancreatic diversion. Roux-en-Y gastric bypass (RYGB) is the most prevalent globallt.¹ However, one of the consequences of bariatric surgeries is that it causes or exacerbates nutritional deficiencies.² Mechanisms that explain why bariatric surgery leads to nutritional deficiencies include alteration to the intestinal anatomy and gut microbial environment as well as dysregulation of enzymes and hormones.³

Most studies on nutritional deficiencies after gastric bypass examine deficiencies of vitamin B₁₂, vitamin B₉, vitamin D, calcium and iron.^4–12 For instance, one systematic review and meta-analysis of 46 studies found folate and B₁₂ as the most prevalent deficiencies with their longest follow-up being 6 years after RYGB surgery.⁵ However, some studies have investigated other micronutrient deficiencies such as vitamin A, vitamin E, selenium and zinc.^13–15 A review of 82 studies found vitamin A and E deficiencies ≥24 months after RYGB surgery.¹³ One review that looked at nine studies found a prevalence of 16% of selenium deficiency at 1-year follow-up.¹⁴ While another systematic review concluded that clinically relevant zinc deficiency is rare and routine monitoring may be unnecessary.¹⁵ Nevertheless, few studies have looked at follow-up >10 years after RYGB. One review of 34 studies reported a prevalence of 54% of secondary hyperparathyroidism >10 years after RYGB.⁹ Our case is unique as it presents a patient with various micronutrient deficiencies >10 years after RYGB.

Nutritional deficiencies can manifest as skin lesions, weakness, nausea, vomiting, diarrhoea, anaemia, ataxia, hair loss and Wernicke’s encephalopathy.¹⁶ However, these manifestations can be misinterpreted as symptoms of other illnesses, such as autoimmune or malignant diseases. Arriving at a diagnosis of micronutrient deficiency can be done by comprehensively understanding the medical and surgical history of the patient. Therefore, there should be a high suspicion of micronutrient deficiencies in patients with a history of bariatric surgery and multiple systemic symptoms (ie, ataxia, rash, anaemia, diarrhoea).

Case presentation

A woman in her 50s with a history of RYGB over 10 years prior to admission (surgery report of the RYGB was not available due to lack of documentation from outside hospital), gallstone pancreatitis, cirrhosis of unknown aetiology, hypertension, diabetes mellitus type 2, hypothyroidism and stress-induced cardiomyopathy with normal ejection fraction presented to the emergency room with 1 week of worsening generalised weakness as well as a diffuse, pruritic and painful desquamating rash. The patient endorsed a 13.6 kg weight loss with nausea, abdominal pain, diarrhoea, loss of taste, arthralgias and chills over the past 3 weeks. Patient’s dietary history or supplement intake prior to admission was not available. She did not have a fever, recent trauma or mucosal involvement of rash. She denied a history of similar rash, immunocompromised state, new environmental exposures, recent travel or insect bites.

The patient was hospitalised 2 months prior to admission for Campylobacter jejuni gastroenteritis, which may have occurred due to small intestinal bacterial overgrowth (SIBO). However, it is also possible that the patient acquired a gastrointestinal (GI) infection from something she ate as the patient reported eating at several other restaurants prior to her presentation. Nevertheless, the patient does not have a history of GI issues and her workup for her diarrhoea only demonstrated a GI PCR positive for C. jejuni and a normal CRP and procalcitonin.

On presentation, the patient was afebrile with a blood pressure of 80/55 mm Hg, heart rate of 99 beats/min and oxygen saturation of 98% on room air. The patient’s body mass index was 20.36 kg/m². Physical examination was notable for dry mucous membranes and generalised abdominal tenderness to palpation without peritonitic signs. A superficial desquamating rash was noted on the bilateral upper and lower extremities, upper back and lower abdomen with areas of superficial erosion on bilateral antecubital fossa (figure 1).

Figure 1.

Before and after nutritional supplementation.

Initial laboratory tests were suggestive for sepsis, including elevated procalcitonin, lactic acid and C reactive protein as well as elevated glucose and thyroid-stimulating hormone (TSH) (table 1). However, there were findings of poor medication compliance for the patient’s underlying hypothyroidism and diabetes mellitus type 2, explaining the intense hyperglycaemia and changes in the thyroid hormones on admission. Imaging was significant for moderate volume ascites, anasarca and edematous appearance of the small and large bowel with mild stranding and wall thickening. The patient was admitted for management of sepsis, weakness and a desquamating rash of unknown aetiology.

Table 1.

Index hospitalisation laboratory values

Laboratory tests	Laboratory values	Reference range
Procalcitonin	5.03 ng/mL	<0.1 ng/mL
Lactic acid	6.2 mmol/L	0.3–1.5 mmol/L
C reactive protein	23 mg/L	0–5 mg/L
Total creatine kinase	73 U/L	<420 U/L
White cell count	4.0×109 /L	4.0–10.0×109 /L
Haemoglobin	125 g/L	130–165 g/L
Platelets	185×109 /L	150–450×109 /L
Albumin	2.7 g/dL	3.5–5.2 g/dL
International normalized ratio (INR)	1.3	0.8–1.1
Aspartate aminotransferase	19 IU/L	0–37 IU/L
Alanine transaminase	60 IU/L	0–35 IU/L
Alkaline phosphatase	171 IU/L	33–133 IU/L
Glucose	416 mg/dL	65–99 mg/dL
Thyroid-stimulating hormone (TSH)	31 mIU/L	0.4–5.0 mIU/L
T4	0.66 ng/dL	0.6–1.20 ng/dL
Vitamin A	0.09 mg/L	0.30–1.20 mg/L
Vitamin B1	70 nmol/L	70–180 nmol/L
Vitamin B3	5.02 µg/mL	0.50–8.45 µg/mL
Vitamin B6	11.1 nmol/L	20–125 nmol/L
Vitamin B9	>20.0 ng/mL	>5.8 ng/mL
Vitamin B12	>1500 pg/mL	180–914 pg/mL
Vitamin C	40 µmol/L	20–114 µmol/L
Vitamin E	3.5 mg/L	5.5–18.0 mg/L
Zinc	33.5 µg/dL	60–120 µg/dL
Copper	35.8 µg/dL	80–155 µg/dL
Total protein	5.8 g/dL	6.4–8.3 g/dL
Prealbumin	Undetectable	20–40 mg/dL
Albumin	2.7 g/dL	3.5–5.2 g/dL
Tissue transglutaminase	<2 U/mL	0–3 U/mL
Antinuclear antibodies IgG	<1:80	<1:80
Anti-double stranded DNA IgG	<1:10	<1:10
C3 complement	45 mg/dL	87–200 mg/dL
C4 complement	16 mg/dL	13–50 mg/dL
Anticardiolipin IgG	<9.4 U/mL	≤20 GPL U/mL
Anti-smith IgG 2 units	2 units	0–19 units
Lyme disease Ab/total with reflex	0.37 IV	≤0.9 IV
HIV fourth-generation antigen/antibody	Negative	Negative
Syphilis treponemal antibodies	Negative	Negative
Nucleic acid amplification for Chlamydia Trachomatis	Negative	Negative
Nucleic acid amplification for Neisseria Gonorrhoeae	Negative	Negative

Investigations

Infectious workup revealed blood cultures that were positive for methicillin-resistant Staphylococcus aureus for which intravenous antibiotic was initiated. A transthoracic echocardiogram showed no evidence of vegetation. Dermatology was consulted for the skin rash, and they recommended a punch biopsy as well as obtaining micronutrient levels due to concerns for nutritional deficiency. Punch biopsy was compatible with nutritional deficiency showing confluent parakeratosis and necrotic keratinocytes scattered throughout the epidermis and areas of slight dysmaturation as evident by suprabasal mitoses. Vitamins A, B1, B₆, C and E as well as zinc, copper, and proteins were deficient (table 1). Pancreatic elastase was <10 (less than 100 μg/g is severe insufficiency) and faecal fat was normal. Given her diarrhoea, a GI PCR panel was ordered and showed no organisms. Burn surgery was consulted and recommended no surgical intervention. Wound specialists were also consulted, and they provided wound care recommendations, such as daily barrier ointments.

Differential diagnosis

Our differential diagnosis was initially expansive given the patient’s non-specific presentation. Autoimmune aetiologies were considered given the patient’s sex, arthralgias, diffuse rash and fatigue. Systemic lupus erythematosus (SLE) was considered; however, antinuclear antibodies IgG, antidouble-stranded DNA, IgG, anticardiolipin IgG, anti-smith IgG and C4 complement were within reference range (table 1). The patient’s C3 complement was low, but the most sensitive and specific tests were used to rule out SLE. In addition, she did not present with common symptoms such as mouth ulcers, malar rash, chest pain, kidney disease and fevers. Further evaluating autoimmune causes of the patient’s rash, coeliac disease was considered because it can affect nutrient absorption resulting in micronutrient deficiencies. However, it was ruled out using tissue transglutaminase, which was within reference range (table 1).

Infectious aetiologies, such as Lyme disease, rocky mountain spotted fever and staphylococcal scalded skin syndrome, were considered. The patient denied new environmental exposures, recent travel, or insect bites. Lyme disease testing was negative (table 1). Sexually transmitted diseases with cutaneous manifestations were considered, particularly HIV, disseminated gonococcal syndrome, syphilis and Chlamydia trachomatis. Laboratory tests were performed and unremarkable (table 1).

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome was considered; however, the patient denied starting a new medication 2–8 weeks before presentation. She did not take any medications that are frequently associated with DRESS syndrome such as antiseizure medications, allopurinol or antibiotics. In addition, she did not have characteristic features such as eosinophilia, atypical lymphocytosis, acute hepatocellular injury, worsening renal function or lymphadenopathy.

Refeeding syndrome (RFS) is an essential consideration since the patient had unintentional weight loss and little or no nutritional intake. Hypophosphataemia, hypokalaemia and hypomagnesaemia should raise suspicion of RFS, but were absent in this case. Precautions were taken to ensure the patient would not develop RFS when initiating diet, such as monitoring laboratory values and slowly starting nutritional repletion. Patients with RFS may present with symptoms ranging from nausea, lethargy to respiratory failure, arrhythmias and death. However, the patient’s symptoms initially improved in response to the intensive nutrition regimen without electrolyte derangements, therefore, excluding the diagnosis.¹⁷

In addition, the patient’s serum reductions of several micronutrients may be due to the patient’s recent episode of possible SIBO. However, she did not have the common vitamin deficiencies seen in SIBO such as vitamins B₁₂ and D.¹⁸ In this case, micronutrient deficiencies are likely due to altered anatomy from RYGB leading to altered absorption as well as the patient’s reduced oral intake.

Treatment

A nutrition support team was consulted, and her nutrition deficiencies were managed with daily intravenous vitamin transfusions, which included zinc chloride 30 mg, copper chloride 4000 μg, vitamin B₉ 1 mg, vitamin B₁ 500 mg, vitamin B₆ 100 mg and vitamin C 1000 mg. Daily oral vitamin D₃ 50 μg, vitamin A capsule 20 000 units and vitamin E capsule 450 mg were provided. Weekly oral vitamin D₂ capsule 1.25 mg and multivitamin tablet were provided. Zinc oxide 40% paste and vitamin A cream were applied at least two times per day. Additionally, oral supplementation included protein supplementation shakes three times per day. There was a concern that she had malabsorption of fat-soluble vitamins secondary to exocrine pancreatic insufficiency, so she was also started on pancrelipase three times per day.

The patient did not receive oral replacement therapy for some nutrient deficiencies because there was a concern of malabsorption early on in the admission due to the patient’s low-normal citrulline level of 23. Citrulline is a biomarker for malabsorption. Therefore, we did not pursue oral repletion and repleted intravenously.

Outcome and follow-up

During the patient’s admission, her symptoms initially improved in response to the intensive nutrition regimen described previously. For instance, the patient’s rash became less diffuse, erythematous and desquamating, with the return of the patient’s original skin tone (figure 1). Also, the patient’s appetite and oral intake increased, and diarrhoea improved. Her admission continued for another few weeks due to the need for intravenous antibiotics, nutrition supplementation and need for intermittent vasopressors. Unfortunately, a month into her admission she developed refractory hypotension and was transitioned to the intensive care unit where she was found to have pulmonary oedema. She died shortly after from cardiac arrest related to pulmonary oedema, despite resuscitation efforts.

Discussion

Restrictive-malabsorptive procedure

Bariatric surgery alters gastric and intestinal anatomy leading to defective nutritional absorption. Therefore, many patients are susceptible to micronutrient deficiencies. RYGB is a restrictive-malabsorptive procedure that isolates a small functional pouch at the top of the stomach that directly connects to the jejunum, allowing food to bypass most of the stomach and the entire duodenum.¹⁹ The procedure is considered both restrictive and malabsorptive. It results in a significant reduction in the surface area of the stomach and duodenum, which reduces the amount of nutrition absorbed.²⁰ Trace metals, such as iron, calcium, magnesium and zinc, are absorbed in the duodenum, which is completely bypassed leading to metal deficiencies.²¹

The procedure is malabsorptive because nutrients are not exposed to fluids that allow nutrients to be absorbed by the small intestine. For instance, nutrients are not exposed to bile which is excreted from the ampulla of Vater in the duodenum. Bile acids are essential for the absorption of lipophilic molecules including fats and fat-soluble vitamins A, D, E and K. In RYGB patients, bile does not encounter food until the food reaches the distal jejunum.²² Therefore, patients with RYGB may become deficient in fat-soluble vitamins and fats. Water-soluble vitamins, such as vitamins B₁₂, B₁, C and B₉, have also been shown to be at risk for deficiency in patients with gastric bypass.¹⁹ For instance, RYGB impairs vitamin B₁₂ metabolism by affecting gastric acid production, therefore, affecting the release of vitamin B₁₂ from cobalamin-R-binding proteins and decreased production of intrinsic factor.

Clinical manifestations of micronutrient deficiencies

Our case exhibits a rare presentation of vitamin, mineral and protein deficiencies with correlating clinical symptoms:

Fat-soluble vitamin deficiencies

Fat-soluble vitamins include vitamins A, D, E and K. The patient in our case had vitamin A and E deficiencies. Vitamin A deficiency presents with acne, dry hair, fatigue, growth impairment, insomnia, hyperkeratosis, immune impairment, night blindness and weight loss.²³ The patient presented with hyperkeratosis (revealed in skin biopsy), immune impairment and weight loss. Vitamin A deficiency in bariatric patients has shown to be resistant to supplementation.²³ Studies have demonstrated prophylactic supplementation of vitamin A did not prevent deficiency after distal RYGB for 10% of patients after 4 years.²⁴

Vitamin E deficiency manifests as gait disturbances, poor reflexes, loss of position sense, loss of vibration sense and shortened red blood cell life.²³ This patient experienced gait disturbances on presentation. Vitamin E deficiency is not common in bariatric surgery patients.²³ For instance, a study showed serum vitamin E levels were normal in patients at 1 year and remained normal in 96% of the patients up to 4 years after bariatric surgery.²⁵ However, the patient had surgery more than 10 years ago, demonstrating possible long-term depleting effects of RYGB on vitamin E stores.

Water-soluble vitamin deficiencies

Water-soluble vitamins include B vitamins and vitamin C. Thiamine, or vitamin B₁, deficiency can lead to confusion, constipation, digestive problems, irritability, loss of appetite, memory loss, nervousness, numbness of hands and feet, poor coordination, and weakness.²³ This patient experienced symptoms of diffuse upper and lower extremities weakness, poor gait, diffuse abdominal pain, impaired appetite and anxiety which correlated with vitamin B₁ deficiency.

Vitamin B₆ can cause anaemia, arthritis, depression, dizziness, impaired wound healing, excessive tearing, angular palpebritis, conjunctiva, angular cheilitis, hypertrophied papillae, irritability, loss of appetite, mouth lesions and nausea.²³ The patient presented with several symptoms of vitamin B₆ deficiency, including impaired appetite and anaemia.

After bariatric surgery, the incidence of vitamin B₁ and B₆ deficiencies are reportedly low.²³ One study found only 29 cases of thiamine deficiency out of 168 010 cases of bariatric surgeries.²⁶ Most studies show clinical symptoms of thiamine deficiency within 2–3 months of bariatric surgery. However, our case demonstrates manifestations of thiamine deficiency over a decade after surgery.²³

Mineral deficiencies

In addition to vitamin deficiencies, this patient had zinc and copper deficiencies. Zinc deficiency presents with acne, amnesia, apathy, brittle nails, depression, diarrhoea, eczema, fatigue, growth impairment, hair loss, hair colour changes, loss of appetite, loss of sense of taste, low stomach acid, nail deformity, immune deficiencies, upper respiratory infections, decubitus ulcers, eye lesions, night blindness and wound healing impairment.²³ This patient presented with loss of appetite and immune deficiencies. Zinc deficiency is common among bariatric patients, so supplementation and monitoring is recommended.

Copper deficiency presents as anaemia, neutropenia, leucopenia, pancytopenia, depression, diarrhoea, fatigue, fragile bones, hair loss, weakness, altered pigmentation of the skin, hypothermia, reduced resistance to infections, cardiomyopathy, connective tissue breakdown and neurological symptoms (polyneuropathy, paresthesia, myelopathy).²³ Out of all these symptoms, this patient had leucopenia, fatigue, skin texture changes, skin pigmentation, weakness and a rash. Interestingly, copper deficiency has not been widely reported in bariatric patients.

Protein deficiency

Protein deficiency manifests as hypoalbuminaemia, anaemia, oedema, asthenia, delayed wound healing, wasted appearance and alopecia.²³ The patient demonstrated most aspects of protein deficiency, for instance, she had hypoalbuminaemia and low levels of total protein (table 1). Additionally, the patient had anaemia with a haemoglobin of 125 g/L (normal: 130–165 g/L).

Lastly, this patient displayed upper and lower extremity oedema and asthenia. RYGB patients experience protein deficiency for various reasons, such as poor oral intake and malabsorption. Protein deficiency is a common complication of RYGB. In fact, at a minimum of 2 years after RYGB surgery, 13% of the patients were found to have hypoalbuminemia and required parenteral nutrition for severe protein malnutrition.²⁴

To summarise, the patient’s complicated hospital course was attributed to her severe malnutrition. The development of her rash was likely due to vitamin A deficiency and copper and zinc deficiencies increased her susceptibility to infections. During the admission, she developed refractory hypotension despite being on multiple pressors, which was likely secondary to cardiogenic shock. She died from cardiac arrest related to pulmonary edema. The patient’s evolution to death could have also occurred due to worsening of her underlying stress-induced cardiomyopathy as her body was under significant stress. By screening as recommended by the American Society for Metabolic and Bariatric Surgery, micronutrient deficiencies can be detected in a timely manner, thus preventing more serious complications, including death.²⁷

Learning points

• Certain vitamin and mineral deficiencies may manifest multiple years after bariatric surgery.

• Patients may need lifelong broad vitamin, mineral and protein supplementation as deficiencies can occur years after bariatric surgery.

• Clinical manifestations of nutritional deficiencies are non-specific and may present similarly to other diseases, prolonging diagnosis.

• Deficiencies may be further exacerbated in the setting of inadequate oral intake, changes in intestinal absorption over time, poor access to healthcare and medication non-compliance.

Ethics statements

Patient consent for publication

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