Pellagra as a differential diagnosis in the confused patient on the acute medical unit

Abstract

A man in his 80s was admitted via the acute medical take after presenting with increased confusion and features of alcohol withdrawal. He had a several-month history of a worsening pruritic rash surrounding his neck, arms and legs in addition to new, profuse diarrhoea. In view of the background of known chronic alcoholism and the coexisting symptoms of rash, confusion and diarrhoea, pellagra was diagnosed via a multidisciplinary approach. Oral nicotinamide supplementation was commenced and his symptoms responded rapidly. The bias and challenge of reaching a unified diagnosis in the context of a multisystem condition are exemplified in this case report.

Background

When patients present with a variety of presenting symptoms, it can often be difficult to distinguish whether they are separate symptoms requiring investigation and management, or whether they indicate manifestations of the same multisystem condition. This is further complicated when many comorbidities exist within a patient’s history, when polypharmacy exists and when patients are frequently admitted with similar presentations. Differentiating symptoms and prioritising them can become difficult. Diagnostic bias can occur, for example, when a patient is known to recurrently present with alcohol intoxication or withdrawal and the current presentation is then attributed as acute exacerbation of a known chronic problem.

In this case report, we are reminded that each presenting symptom may indicate manifestations of the same condition. When evaluating a patient’s current admission, we should aim to use the same detailed approach as that of a patient presenting for the first time to maximise the chance of reaching the correct diagnosis. In this case, the patient had a skin condition, that although rare in the UK, is endemic in some parts of the world.

Pellagra is a clinical syndrome attributable to niacin (vitamin B₃) deficiency. Historically, a poor diet has been the main cause, and while this remains the case in less economically developed countries, it is almost unheard of as a cause in developed regions. The leading cause in developed countries is chronic alcoholism followed by anorexia nervosa and drug-induced niacin deficiency.¹ Pellagra is considered a photosensitive dermatitis; however, the molecular mechanisms underpinning the relationship between niacin deficiency and photosensitivity are yet to be fully established.²

As illustrated in figure 1,³ pellagra classically manifests as the four ‘Ds’: dermatitis, diarrhoea, dementia, and if untreated, death.⁴ In isolation, diarrhoea, dementia (acute or chronic confusion) and rashes are common presenting symptoms on the acute medical take. The neurocognitive impairment in pellagra is historically described as a ‘dementia’; however, ‘delirium’ may be a more accurate description.⁵ Patients who present with alcohol withdrawal syndrome may have associated confusion and in severe cases, delirium tremens.⁵ Dementia is likely to be a longer-term manifestation of niacin deficiency, and a minority of patients present with the classic presenting features.⁵ This already poses a diagnostic challenge due to the multifactorial reasons someone with alcohol excess may present confused, be it acute or chronic.

Figure 1.

The four ‘Ds’ representing the classic clinical manifestations of niacin deficiency. Adapted from Boloor and Nayak.³

We report a case of pellagra in a patient with a several decade-long history of alcohol dependence. Our case illustrates the importance of having a broad-minded approach when assessing patients while objectively considering each symptom and the whole picture to identify possible differential diagnoses, rather than attributing recurrent presentations and/or symptoms to that of previous hospital presentations or known chronic conditions, in this case, alcohol addiction.

Case presentation

A man in his 80s was admitted to the acute medical unit with his wife reporting concern regarding a change in his behaviour. He had a 50-year history of alcohol dependence, drinking over 35 units per week. On admission, he was started on an alcohol detoxification regimen and the confusion attributable to withdrawal settled within 48 hours. When asked, the patient believed the reason for his admission was due to ‘itchy skin’. He had a scaly, pigmentated rash on the anterior neck and circumferentially on the arms and legs that had been causing significant trouble with his sleep (figures 2–4). Despite a reported 2-week period of abstinence in the month prior to his admission, his coping mechanism for evening pruritus had been to increase his alcohol consumption in the days prior to admission. Once his initial confusion had improved, the longer-standing cognitive impairment reported by his wife led to a further work-up for his confusion, alongside further investigations with regard to his rash, which appeared quite extensive around his neck. An inpatient dermatology opinion was sought, medical photography undertaken and with consideration of the history of alcoholism, a diagnosis of pellagra was subsequently made. To note, he did not have any oral mucosal manifestations of malnutrition.

Figure 2.

Symmetrical dry scaly rash of the legs with areas of hypopigmentation.

Figure 3.

Symmetrical pigmented scaly rash in a necklace distribution on the anterior neck and chest with associated erythema (anterior view).

Figure 4.

Symmetrical pigmented scaly rash in a necklace distribution on the anterior neck and chest with associated erythema (lateral view).

Our patient had been known to local dermatology services since 2007 (figure 5). On this admission, his wife reported that the current rash was the most severe she had seen, and that its onset had coincided with a spell of severe diarrhoea, that is, his symptoms had changed. Our patient was retired, spent much of his time indoors and had not travelled overseas in recent months; however, previous occupational or long-term sun exposure remains unknown. The patient’s confusion, also reported by his wife, was a recent change although he had previously suffered from alcohol-related paranoid delusions. When revisited, there was a clear history over recent months of the emergence of a new rash, new onset confusion and new extensive diarrhoea, with bowel motions up to 10 times per day.

Figure 5.

Timeline of dermatology clinic appointments and the diagnosis stated at each.

In the preceding 10 years, the patient had been seen by a number of dermatologists and received diagnoses of ‘eczematous dermatitis’, ‘lichen simplex chronicus’ and ‘excoriated nodular prurigo’ (figure 5). On reviewing previous medical records and documentation, the affected skin involved the arms, legs, nape of the neck and groin, which are the areas typically involved in pellagra. Each consultation documented a continued poor response to a combination of topical agents and oral prednisolone. It is possible that diagnostic overshadowing may have contributed to a delayed diagnosis. It is also difficult to tell whether his rash had changed in appearance from these pre-existing diagnoses due to a lack of access to medical records and collateral information as previously referenced.

Investigations

Pellagra is a clinical diagnosis based on the four ‘Ds’ alongside evidence of factors that may contribute to niacin deficiency, for example, alcohol addiction. Vitamin B₃ levels are not routinely measured in UK hospitals as part of the diagnostic work-up. The diagnosis was made by a dermatologist after review of both the clinical photographs (figures 2–4) and a summary of the patient’s presentation, background and history obtained by the acute medicine team.

Differential diagnosis

In the UK, pellagra is rare. Although the incidence of pellagra in the UK is poorly documented, its rarity implies it affects fewer than 1 in 2000 people.⁶ Many general medical physicians and junior doctors assessing and managing the care of patients on the medical take in UK hospitals may not have seen a diagnosis of pellagra before. As such, this may result in the diagnosis being missed and is unlikely to be included in a list of differential diagnoses. Of the four ‘Ds’ of pellagra, admitting physicians frequently see confused patients either with an acute delirium or dementia diagnosis, as well as diarrhoea. The rash is often what clinches the diagnosis due to its pathognomonic distribution and appearance. Dermatologists would often be the first specialty to make this diagnosis, being more familiar with its appearance. Therefore, seeking specialist advice and review is essential for the diagnosis of this condition. Alongside the possibility of pellagra, it is important to exclude other mucocutaneous manifestations of photosensitivity including systemic lupus erythematosus, drug-induced photosensitivity and porphyrias, all of which can cause confusion too.

Treatment

Our patient was admitted for alcohol detoxification and commenced on the Clinical Institute Withdrawal Assessment alcohol protocol in accordance with our local trust policy.⁷ In addition to chlordiazepoxide, he also received six pairs of Pabrinex daily via intravenous infusion, amounting to 960 mg niacin (vitamin B₃) per day. Following intravenous Pabrinex for 5 days, the patient was started on oral nicotinamide 500 mg two times per day for 4 weeks. He was prescribed lifelong oral thiamine supplementation, and the importance of cutting down on his alcohol consumption was also reiterated.

Outcome and follow-up

Our patient was followed up by dermatology 1 month after his acute admission and initial diagnosis of pellagra. His symptoms had significantly improved with niacin supplementation; however, he continued to suffer from burning pain over the affected areas of skin. This was treated with topical emollients and steroids. His wife also reports that his alcohol consumption has now reduced to ~14 units per week.

Discussion

Pellagra is defined as a deficiency of niacin (vitamin B₃) and can be the result of malabsorption, excessive gastrointestinal (GI) loss, decreased intake, metabolic derangement or it can be drug induced.⁸ Nutritional deficiency causes primary pellagra while the secondary causes are unrelated to dietary deficiency (figure 6).⁹ Human niacin requirement is obtained through dietary intake, mostly acquired directly from foods rich in niacin and the remainder synthesised from tryptophan, an essential amino acid. Dietary sources rich in niacin include liver, fish, eggs, milk, nuts and avocados.¹ Niacin is a precursor for two coenzymes (nicotinamide adenine dinucleotide (NAD) and NAD-phosphate), crucial for cellular metabolism and DNA signalling.⁸

Figure 6.

Causes of primary and secondary pellagra.

The relationship between alcohol and nutritional deficiency is twofold. First, alcohol is deficient in nutrients but for many with alcohol dependency, it is their primary source of dietary calories. Second, alcohol destroys duodenal villi thereby impeding absorption in the GI tract- this may be exacerbated by the severe diarrhoea characteristically seen in patients with pellagra.⁵ Ultimately, while niacin can be replaced with supplements, it is cessation of alcohol intake that will treat pellagra in this patient cohort, in order to treat the underlying pathophysiologythat is, a direct result of alcohol excess.

Although endemic in India, China and parts of Africa, pellagra is almost eradicated in Western countries due to food product fortification.¹⁰ When a diagnosis is suspected, prompt treatment with oral nicotinamide is crucial and has the potential to be lifesaving.⁸ The British National Formulary does not list oral nicotinamide, reflecting the scarcity of cases in the UK. In each case, the prescribed dose of nicotinamide supplementation should be discussed with pharmacist and dermatologist colleagues. In this case, 500 mg two times per day for 4 weeks was advised.

We previously mentioned that ‘diagnostic overshadowing’ may have contributed to a delayed diagnosis in our patient. This phenomenon alludes to individuals with pre-existing mental illness receiving a lack of focus on their physical symptoms where instead, their symptoms are misattributed as a manifestation of continued mental illness.¹¹ In our case, given the extensive history of alcohol dependence, detoxification was the initial primary medical focus. This perhaps prevented the early recognition of the relationship between alcohol intake and dermatological disease. Furthermore, our patient had been seen by dermatologists in the past (figure 5), yet the corresponding medical records made no mention of alcohol dependency. This further demonstrates the importance of a holistic approach needed by all clinicians in assessing patients, including taking a full social history as this may well help prompt rarer diagnoses. This may be attributed to the fast-paced nature of the outpatient clinic setting; however, for the admitting and treating medical team reading these letters, it was assumed that the patient’s rash was an isolated issue and therefore not something that needed to be dealt with initially on this acute admission. With alcohol withdrawal being such a common presentation among medical admissions, the focus was on preventing seizures, managing tachycardias and the adverse physical features of alcohol withdrawal, instead of considering broader differentials for the coexisting rash and confusion. Potential factors contributing to diagnostic overshadowing include the unfortunate prevalent stigma surrounding mental illness (including alcohol addiction), challenges in establishing a clear medical cause for the symptoms, and a possible lack of experience and expertise.¹¹ The latter may be particularly apparent on the acute medical take where patients are often seen by junior and senior doctors, neither of whom are dermatology specialists.

Our case shows that although rare, pellagra in Western societies exists and therefore should be considered through holistic assessment of patients, be it in an outpatient diagnostic clinic environment or acutely on the medical take. Chronic alcoholism was the secondary cause in our patient’s case where he presented with dermatitis, delusions and diarrhoea, three of the four classic features of pellagra. Fortunately, this was not a fatal case owing to the rigorous attention to the patient’s history and the holistic focus and timely actions of the multidisciplinary team.

Patient’s perspective.

When my daughter and I heard about this rare skin disease, we researched it the same evening and we couldn’t believe what we were reading. So many of the symptoms listed were exactly what my husband has been experiencing. He has seen so many dermatologists over the years, but this has never been picked up. We are so glad that on this hospital admission, all his problems have been considered and he is receiving thorough care. We are so thankful.

Learning points.

• This report is a textbook case of pellagra comprising three of the four ‘Ds’ (dermatitis, diarrhoea, dementia/delirium, death).

• Utilisation of the multidisciplinary team, in this case, medics, alcohol liaison and dermatology, is imperative to deliver prompt care and prevent a potentially fatal condition.

• Diagnostic overshadowing in patients with pre-existing mental illness may lead to a delayed diagnosis of physical symptoms.

• Multimorbid patients should be reviewed holistically during acute medical admissions to ensure each of their comorbidities are not in fact correlated with, and/or symptoms of an underlying pathology.

Ethics statements

Patient consent for publication

Obtained.