Cutaneous Manifestations of Nutritional Deficiency: A Harbinger of Potential Mortality

While nutrition is an important part of medicine, its role in the field of dermatology remains relatively unclear. Various studies have examined the role of diet in dermatologic disease severity, development, and progression, with mixed results. It is well known that nutritional deficiencies can have cutaneous manifestations, but this area remains under-researched and underappreciated within dermatology.

“If the adages ‘you are what you eat’ and ‘the skin is the largest organ in the body’ are true, then what we eat really dictates how healthy our skin is,” said Jonathan J. Lee, MD, a dermatopathology fellow at the Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, in an interview with The Dermatologist.

Dr Lee and colleagues at the University of Pittsburgh Medical Center, PA, have been working to shed more light on this connection. This research had its genesis when Dr Lee was a junior dermatology resident on the inpatient consult service. He was asked to evaluate an otherwise largely healthy-appearing female patient with a dry, desquamative eruption with a predilection for sites of friction. He suspected that it may be due to zinc deficiency. “We recommended management, as anyone normally would, with zinc replacement and outpatient follow-up,” he said.

However, the patient was readmitted about 1 month later with progression of her skin condition to a Stevens Johnson syndrome-like state that was confirmed to be nutritional deficiency upon biopsy. “She suffered a really terrible, precipitous course and ultimately passed away from what I suspect was a combined micronutrient deficiency,” said Dr Lee. “This case really struck me, because initially I thought ‘wow she looks totally fine,’ and then a couple of weeks later she returned in a much worse condition despite the recommended treatment,” he added.

Skin Findings Associated With Nutritional Deficiency

Dr Lee wanted to investigate whether this scenario was common among patients with nutritional deficiency or if his experience was unique. With the support of his faculty, including Timothy Patton DO, Arthur Huen, MD, PhD, Jonhan Ho, MD, MS, and Joseph C. English, III, MD, and trainees Sara Mater (MS-III) and Carlos Morillo-Hernandez (MS-III) in the department of dermatology at the University of Pittsburgh Medical Center, Dr Lee conducted a retrospective cohort study, carefully evaluating the medical records of 18 patients with cutaneous manifestations of nutritional deficiency with laboratory confirmation from January 1, 2005 through December 31, 2017. They assessed data on their clinical presentation, comorbidities, laboratory values, skin biopsy findings, and clinical outcomes. Their study revealed an alarmingly high mortality rate among patients with zinc and protein deficiencies.¹

Dr Lee and his colleagues found that patients often presented with erythematous to hyperpigmented, geometric to stellate patches and thin plaques favoring acral and extremity skin (Figure). Occasionally, serpiginous borders were seen. There was a predilection towards areas of friction, they noted, as intertriginous sites were frequently involved, including the inguinal folds, medial thighs, gluteal cleft, perianal skin, and axillae. In addition, they noted facial involvement of the periorificial (around the mouth, nose, and eyes) and, less commonly, auricular skin.

Figure. Clinical manifestations of acquired malnutrition dermatosis. (A) Serpiginous, erythematous to hyperpigmented plaques with surrounding erythema on the dorsal feet of a 66-year-old African American man with a history of untreated hepatitis C, low zinc, and hypoalbuminemia. (B, C) Desquamating dry pink patches and plaques on the hands and perianal skin with flaky paint-like scale in a 53-year-old morbidly obese man on dialysis with zinc deficiency, hypoalbuminemia, and low niacin. (D) Symmetric, hyperpigmented, desquamating and eroded patches on the inner thighs and labia of a 44-year-old African American woman with a remote history of Roux-en-Y gastric bypass, low zinc, hypoalbuminemia, niacin, and thiamine deficiency. Note that lesions appear apposed symmetrically in “kissing” fashion due to friction and skin fragility.

Secondary dermatologic changes ranged from dry, enamel-like flaky, paint-like, or psoriasiform scale to weepy, flat vesicobullae, erosions, or wet sheets of desquamation. “An erythrodermic (4 [22%]) or Stevens-Johnson syndrome/toxic epidermal necrolysis-like presentation (3 [17%]) was not uncommon,” the researchers added. Other commonly associated signs and symptoms included profound lower extremity edema or anasarca with fatigue, diarrhea, dyspnea on exertion, anorexia, and weight loss.

Importantly, skin biopsies from these patients demonstrated the classic epidermal pallor diagnostic for nutritional deficiency in only 7 of 18 patients (39%). The remaining patients had spongiotic, psoriasiform, or atrophic epidermal patterns with overlying confluent parakeratosis and intracorneal splitting, the researchers said. “This finding that nonclassic biopsy results predominate is extremely important because clinicians must use a high index of suspicion to make this diagnosis despite a non-confirmatory or false-negative biopsy result,” added Dr Lee. “The biopsy findings are very likely to be influenced by where within the lesion or lesions the sample is taken or the time course of the disease state at which it is taken and so multiple biopsies, as is done for conditions such as mycosis fungoides, may be indicated to help diagnose this condition.”

Among the 18 patients, eight were morbidly obese of whom six had undergone weight loss surgery, all of which were by Roux-en-Y gastric bypass surgery. “The fact that two of these patients had not yet undergone weight loss surgery was fascinating,” noted Dr Lee, “because we traditionally believed that malabsorptive states, which can be induced by weight loss surgery, were almost a necessity to present with zinc deficiency. But the fact that we are diagnosing zinc and protein malnutrition in the morbidly obese who have not yet undergone the knife raises the concern and possibility that the morbidly obese state not only requires greater micronutrients and protein to maintain the greater body habitus but also emphasizes the potentially fatal end-stage consequences of a life of nutrient-poor dietary intake.”

Other comorbidities included alcoholism (44%), hepatic cirrhosis (44%), hepatitis C infection (28%), large, chronic, postsurgical wounds or decubitus ulcers (22%). Twelve patients had documentation of having “failure to thrive.” In addition, co-occurrence of micronutrient deficiencies was common, particularly zinc and protein (11 [61%]).

Thirteen patients had ultimately died (72%). In detailed review of final clinical source proceedings of seven patients, the researchers found that patients often succumbed to an irreversible nonseptic, distributive, cardiovascular shock with anasarca and multi-organ failure. Patients younger than 50 years had a median survival of 2 months compared with those older than 50 years, who had a median survival of 34 months.

These findings, although alarming, was not surprising given his recent clinical experience, Dr Lee said. In fact, they confirmed his suspicion that they had “unmasked a silent serial killer,” he reflected.

Double Burden of Malnutrition

Malnutrition is a well-known concern among patients who are not eating enough either due to food insecurity or loss of appetite from various conditions, such as cancer. “Failure to thrive”—a more commonly used term among geriatric and pediatric patients with low body mass index (BMI)—was a common characteristic among patients in the study performed by Dr Lee et al.

One of the more surprising findings was the number of patients with obesity who had not undergone bariatric surgery or had an anatomical reason for malabsorption and received a diagnosis of protein or zinc deficiency, Dr Lee noted. “When we see patients with morbid obesity, we can infer that the food they are eating is fulfilling their macronutrient requirements, such as protein, fat, and carbohydrates, but they may not be eating enough foods rich in micronutrients,” Dr Lee said. Although they appear overnourished, micronutrient deficiencies can still occur in these patients. This has been reported in the bariatric surgery literature, he added, where several case reports reported nutritional deficiency among patients with obesity prior to bariatric surgery. This finding is important for dermatologists to keep in mind when seeing patients with obesity, as they can have a micronutrient deficiency even without history of bariatric surgery.

This finding also exemplifies what the World Health Organization calls “the double burden of malnutrition,” where individuals experience nutritional deficiencies at both extremes of BMI.² “There is a subset of the global population that is malnourished from inadequate consumption, and those would fall into the ‘failure to thrive’ category,” said Dr Lee. At the other end, however, is “the ‘westernized problem’ where patients are eating plenty, but plenty of the wrong things and, therefore, they are developing medical problems,” he added. These patients are ‘misnourished,’ as opposed to undernourished, which contributes to conditions associated with consuming a high inflammatory diet, such as metabolic syndrome and cancers, as well as a potentially greater risk for deficiencies in key micronutrients. 

Suspecting Nutritional Deficiency

According to Dr Lee, the anatomic distribution of skin manifestations is a helpful clue for diagnosing nutritional deficiencies. It has a tendency to favor areas of friction or trauma, such as the acral-peripheral regions, such as the hands and feet, and occasionally the facial skin, he said, as well as intertriginous areas, including the lateral thighs, and sometimes the periorificial area. Seborrheic dermatitis-like lesions on the face, such as around the eye and mouth, is one of the many manifestations of nutritional deficiency.

“Nutritional deficiency is something that all clinicians should keep in the back of their mind,” said Dr Lee, because its cutaneous manifestations can mimic other diseases. The differential diagnoses of bilateral hand or foot dermatitis, seborrheic dermatitis, intertrigo, and even psoriasis, among others, should also include nutritional deficiency.

In addition, the index of suspicion for nutritional deficiency should be higher in individuals with known risk factors. Based on their findings, this includes a history alcoholism, malabsorptive states, bariatric surgery, cancer or history of chemotherapeutic treatment, liver disease or hepatitis C, chronic non-healing wounds, obesity, and eating disorders.

Fad diets, such as the 22-Day Nutrition program and juice cleanses, have also been associated with nutritional deficiencies. “We often don’t have time to press patients about their dietary habits, but in the right clinical context, you may venture down that road in conversing with a patient,” said Dr Lee.

Combined Micronutrient Deficiencies and Malnutrition

One fact Dr Lee highlights is the importance for screening for thiamine, or vitamin B₁, deficiency in the work-up and management of these patients. Several in his series appeared to have passed from thiamine deficiency, which can present in many clinical syndromes. These include the so-called wet or dry Beri-Beri and Wernike-Korsakoff syndrome. Wet Beri-Beri results in cardiovascular collapse with profound total body anasarca, said Dr Lee, “which was a common clinical picture we saw with many of these patients, and some of the critical care notes had documented clear cut evidence of confabulation.”

“The key take home is if you suspect a patient is deficient in one nutrient, then they may be deficient in multiple,” said Dr Lee, stressing the importance of conducting a thorough laboratory screening evaluation for patients with suspected nutritional deficiency. Several nutritional deficiencies, such as thiamine, are medical urgencies or emergencies, and can be fatal. Screening for zinc, protein, thiamine, niacin, vitamin B₃ and B₆, among others is important to ensure patients are treated as quickly as possible before irreversible damage or death.

Areas of Future Research: Is It Too Late?

Several aspects of malnutrition in dermatology still require further research to better characterize and manage this condition, including “going back to the basics,” said Dr Lee. Careful review and study of the clinical presentations of patients, how often certain areas of the body are involved, among other aspects are important for documentation and teaching medical students, resident physicians, and other trainees on how to identify these conditions. In addition, his study raised the need for further research into the histopathologic spectrum of nutritional deficiency, as only one-third of patients presented with the classical findings.

Lastly, understanding how to best re-nourish these patients requires more investigation as there is no systematic approach and not many guidelines available, said Dr Lee. “Studying the treatment of these patients is important because based off what we found in our study, and our interpretation, is that, essentially, when a patient presents with cutaneous manifestations of zinc or protein deficiency, it may be too late,” he said. Within the medical community, as well as in dermatology and nutrition, evaluating patients at risk and ensuring they eat properly is important. While dermatologists are not nutrition experts, Dr. Lee stressed the importance of coordinating with nutritionists to better understand how to treat these patients.

“Dermatologists think and take pride in the fact that the skin is the window into our body. Our nutrition is something that we have to study more because, unfortunately, I think we are going to be seeing this more often,” said Dr Lee. While public health efforts are slowly addressing the growing obesity epidemic, cancer and subsequent chemotherapy and other emerging risk factors such as untraditional dietary practices are being noted at an increasing rate in our patients.

One important aspect Dr Lee stressed was the need for collaboration between dieticians, nutritionists, and dermatologists. “I think we need to create a bridge because, as I mentioned before, the skin is our largest organ, and we are what we eat. Therefore, we should be chatting with nutritionists more and collaborating with them in the clinical space and in research,” he added.

“This is something that deserves increased and more careful attention from the [American Academy of Dermatology], as well as from providers and the community,” Dr Lee said, encouraging clinicians to keep in mind the importance of nutrition and skin health. 

References

1. Lee JL, Mater S, Morillo-Hernandez C, et al. Clinical outcomes of hospitalized adult patients with dermatologic manifestations of protein malnutrition and zinc deficiency [published online June 12, 2019]. JAMA Dermatol. doi:10.1001/jamadermatol.2019.0854

2. World Health Organization. Double burden of malnutrition. https://www.who.int/nutrition/double-burden-malnutrition/en/. Accessed August 20, 2019.