Defisiensi Vitamin B3 (Niasin)

01Pathophysiology

Niacin (vitamin B3) serves as the precursor for two essential coenzymes: NAD (nicotinamide adenine dinucleotide) and NADP (nicotinamide adenine dinucleotide phosphate). These coenzymes function as electron carriers in over 400 enzymatic reactions across the body, including glycolysis, the citric acid cycle, oxidative phosphorylation, fatty acid synthesis, and DNA repair pathways. When niacin is deficient, cellular energy production fails broadly, but tissues with high turnover rates and high metabolic demands are affected first.

The body can synthesize niacin endogenously from tryptophan through the kynurenine pathway. Approximately 60 mg of tryptophan yields 1 mg of niacin, and this conversion requires adequate vitamin B6, riboflavin (B2), and iron as cofactors. This is why conditions that deplete tryptophan or block its conversion also produce pellagra. Carcinoid syndrome diverts tryptophan toward serotonin synthesis, leaving insufficient substrate for niacin production. Hartnup disease, an autosomal recessive disorder, impairs neutral amino acid absorption in the intestine and renal tubules, reducing tryptophan availability. Isoniazid depletes pyridoxine (vitamin B6), which is a required cofactor in the tryptophan-to-niacin conversion pathway.

The dermatitis occurs because skin cells exposed to UV radiation sustain DNA damage that requires poly-ADP-ribose polymerase (PARP), an NAD-dependent DNA repair enzyme. Without adequate NAD, UV-damaged keratinocytes cannot repair and undergo apoptosis, producing the characteristic photosensitive, bilateral, symmetric rash in sun-exposed areas. The diarrhea results from mucosal atrophy and inflammation of the gastrointestinal tract, since enterocytes are among the most rapidly dividing cells in the body. The dementia reflects neuronal dysfunction from impaired energy metabolism and neurotransmitter synthesis in the central nervous system, as NAD is also involved in serotonin production from tryptophan.

The reason a corn-based diet causes pellagra is twofold. First, the niacin in corn exists in a bound form (niacytin) that is not bioavailable unless treated with alkali (as in the traditional nixtamalization process used in Mesoamerican cultures). Second, corn is low in tryptophan, eliminating the alternative biosynthetic route. This explains why pellagra was historically endemic in populations relying on untreated maize as a dietary staple.

02Classification and Clinical Manifestation

The clinical progression typically follows the sequence of dermatitis first, then diarrhea, then dementia, though not all three need to be present for diagnosis. In chronic alcoholics, the neuropsychiatric features may predominate and overlap with Wernicke encephalopathy (thiamine deficiency), making differentiation important.

03Diagnostic Workup

Pellagra is fundamentally a clinical diagnosis. The best initial step is recognizing the pattern: a patient with a known risk factor (alcoholism, corn-dependent diet, carcinoid syndrome, isoniazid therapy, or Hartnup disease) presenting with some combination of photosensitive dermatitis, diarrhea, and neuropsychiatric symptoms.

Laboratory confirmation is often pursued but not always necessary in a classic presentation. The most practical biochemical test is measuring urinary N1-methylnicotinamide, a downstream metabolite of niacin. A 24-hour urine collection showing levels below 5.8 micromol/day supports deficiency. However, this test is not universally available, and results take time.

In clinical practice and on exams, the therapeutic trial functions as the most practical confirmatory method. Niacin supplementation produces dramatic improvement in dermatitis and diarrhea within 24 to 48 hours and neuropsychiatric symptoms within days to weeks. This rapid response is itself diagnostic and is a commonly tested concept.

When the dermatitis is the dominant feature and the clinical picture is ambiguous, a skin biopsy may be performed to exclude other photosensitive dermatoses (such as systemic lupus erythematosus or porphyria cutanea tarda). However, the histologic findings in pellagra are nonspecific and not diagnostic in isolation.

One important workup consideration: because pellagra often occurs in the context of global malnutrition or alcoholism, always evaluate for concurrent deficiencies. Thiamine (B1), riboflavin (B2), pyridoxine (B6), folate, and zinc deficiencies frequently coexist and require simultaneous treatment.

04Management and Treatment

Nicotinamide is preferred over nicotinic acid for treatment because it does not cause the prostaglandin-mediated flushing reaction (facial warmth, redness, pruritus) that nicotinic acid produces. Both forms are equally effective at replenishing NAD and NADP stores, but nicotinamide is better tolerated. The standard dose is 100 mg three times daily, continued for three to four weeks or until clinical resolution.

For patients who cannot tolerate oral intake due to severe vomiting or gastrointestinal disease, parenteral nicotinamide at 50 to 100 mg can be administered intramuscularly or intravenously.

The dermatitis responds fastest, often showing improvement within 24 to 48 hours. Diarrhea typically resolves within days. Neuropsychiatric symptoms, particularly dementia, improve more slowly and may take weeks. Long-standing neurologic damage may be only partially reversible, which underscores the importance of early recognition.

Addressing the underlying cause is essential for long-term management. In patients on isoniazid, prophylactic pyridoxine (25 to 50 mg daily) should always be co-administered to prevent niacin depletion through the tryptophan pathway. In carcinoid syndrome, the serotonin-producing tumor must be managed (somatostatin analogs such as octreotide reduce tryptophan diversion). In patients with Hartnup disease, long-term niacin supplementation and a high-protein diet are the cornerstones of prevention.

A key distinction for exam purposes: nicotinic acid at pharmacologic doses (1 to 3 g/day) is used as a lipid-lowering agent to raise HDL and lower triglycerides, which is a completely different clinical context from treating pellagra. The lipid-lowering dose is associated with hepatotoxicity, hyperglycemia, hyperuricemia, and flushing. Do not confuse the therapeutic replacement dose with the pharmacologic lipid dose.

05Differential Diagnosis and Distractors

06Traps and High-Yield Pearls

The most common way students miss pellagra questions is by failing to connect the underlying cause to the deficiency. A vignette will rarely hand you a malnourished patient on a corn diet. Instead, it will present an alcoholic patient with a photosensitive rash and confusion, a tuberculosis patient on isoniazid who develops diarrhea and dermatitis, or a patient with flushing episodes (carcinoid) who later develops a neck rash and cognitive decline. The core competency being tested is your ability to trace the pathophysiologic link from the risk factor to tryptophan/niacin depletion.

Another frequent trap involves confusing pellagra with Wernicke encephalopathy in the alcoholic patient. Both present with neuropsychiatric changes in a malnourished alcoholic. The discriminator is the photosensitive dermatitis and diarrhea in pellagra versus the ophthalmoplegia and ataxia in Wernicke. If the vignette describes a rash, the answer is pellagra. If it describes eye movement abnormalities, think thiamine.

Students also confuse the treatment dose of niacin (100 mg three times daily for pellagra) with the pharmacologic lipid-lowering dose (1 to 3 g/day). A question may ask about side effects: flushing, hepatotoxicity, and hyperglycemia are associated with the high lipid-lowering dose of nicotinic acid, not with the replacement dose of nicotinamide used for pellagra.

Remember that Casal necklace is pathognomonic. If any vignette describes a hyperpigmented, scaling rash distributed around the neck in a collar-like pattern, the answer is pellagra regardless of what other information is presented.

Finally, always recall the tryptophan-to-niacin conversion requires B6 as a cofactor. This is why isoniazid (which depletes B6) causes pellagra indirectly, and why the prevention strategy is to supplement pyridoxine alongside isoniazid, not to supplement niacin directly.