Glucagonoma differential diagnosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Parminder Dhingra, M.D. [2] Mohammed Abdelwahed M.D[3]

Overview

Glucagonoma must be differentiated from certain skin lesions (acrodermatitis enteropathica, psoriasis, pellagra, eczema) and other causes of hyperglucagonemia (infection, diabetes mellitus, Cushing syndrome, renal failure, acute pancreatitis, severe stress, and prolonged fasting).

Differentiating Glucagonoma from other Diseases

Glucagonoma must be differentiated from certain skin lesions in which necrolytic migratory erythema can be found and other causes of hyperglucagonemia:

Disease	Clinical Picture			Investigations	Pictures
	History	Symptoms	Signs
Glucagonoma	A family history of multiple endocrine neoplasia type 1	Necrolytic migratory erythema characterized by the spread of erythematous blisters and swelling across areas subject to greater friction and pressure, including the lower abdomen, buttocks, perineum, and groin.[2] Weight loss[3] Glucose intolerance[4]	Rash: Erythematous, ring shaped rash that blisters, erodes, and crusts over suggesting necrolytic migratory erythema. Muscle atrophy may be present. Unilateral calf or thigh erythema, and swelling. Hyporeflexia Unilateral/bilateral sensory loss in the upper/lower extremity	Serum glucagon[1] Increased plasma glucagon levels (>500 pg/mL).[3] Concentrations above 1000 pg/mL are diagnostic of glucagonoma.[4] CT scans are used to determine the location of the tumor, show the organs nearby. Liver metastases may appear isodense with the liver on a non-contrasted study.[4]
Pemphigus foliaceus	Autoimmune blistering disease of the skin with characteristic lesions that are scaly, crusted erosions, often on an erythematous base.[1] Mucosal involvement is absent even with widespread disease.[2]	The main symptom is a cutaneous lesion that usually develops in a seborrheic distribution:the scalp, face, and trunk are common sites of involvement. The skin lesions may remain localized or may coalesce to cover large areas of skin. Pain or burning sensations frequently accompany the cutaneous lesions. Systemic symptoms are usually absent.	The skin lesions usually consist of small, scattered superficial blisters that rapidly evolve into scaly, crusted erosions Occasionally, pemphigus foliaceus progresses to involve the entire skin surface as an exfoliative erythroderma. Positive Nikolsky sign	Autoimmune IgG build up in the epidermis, then nearly almost all of the antibodies are aimed against desmoglein 1
Pustular psoriasis	Positive family history of psoriasis, frequent association with histocompatibility antigen (HLA)- Cw6.[2] A history of a long-term erythematous scaly area with ocular and joint involvement. Past medical history of the patient may include viral or bacterial infection, diabetes, hypertension, chronic kidney disease and/or obesity.[3]	Pain, which has been described by patients as unpleasant, superficial, sensitive, itchy, hot or burning.  Pruritus High fever Dystrophic nails Recent presentation of arthralgia	Papulosquamous disease with variable morphology, distribution, severity, and course Scaling papules and plaques Koebner phenomenon: appearance of new psoriatic lesions at the site of skin injury Woronoff’s ring: ring of peripheral blanching skin around a psoriatic plaque Auspitz’s sign: small bleeding points are seen upon disruption of a psoriatic scale.	Skin biopsy Perivascular and dermal inflammatory cell infiltration Vascular dilation Absent granular layer Elongation of dermal papillae Parakeratosis Spongiform pustules of Kogoj (pathognomic of psoriasis) Munro's micro abscesses (pathognomic of psoriasis) Edema of dermal papillae Basal cell layer is expanded Leukocytosis
Acrodermatitis enteropathica	An autosomal recessive disorder characterized by periorificial and acral dermatitis, alopecia, and diarrhea. The genetic base is a mutation of SLC39A4 which encodes a transmembrane protein that serves as a zinc uptake protein.	Symptoms appear in infants after breast milk weaning. The appearance of erythematous patches and plaques of dry, scaly skin. Diarrhea may occur.	Erythematous patches and plaques of dry, scaly skin. The lesions may appear eczematous or may evolve further into crusted vesicles, bullae or pustules. The lesions are frequent around natural orifices like the mouth perioral and anus peri-anal, and also in hands, feet, and scalp. paronychia  Alopecia of the scalp, eyebrows, and eyelashes	Measurement of zinc in plasma, erythrocytes, neutrophils, lymphocytes, and hair. A low plasma zinc usually is defined as a value less than 60 mcg/dL. Zinc levels in neutrophils or lymphocytes may be more sensitive than plasma zinc. The criteria for zinc deficiency are decreased zinc level in either lymphocyte. Depressed serum alkaline phosphatase levels for age provide supportive evidence for zinc deficiency.
Pellagra	It is a niacin deficiency disease characterized by a photosensitive pigmented dermatitis, diarrhea, and dementia. Hisotry of alcoholics, bariatric surgery, anorexia nervosa, or malabsorptive disease. Dietary deficiency especially in infants Past history of Carcinoid syndrome Prolonged use of isoniazid A family history of Hartnup disease	Photosensitivity Pigmented dermatitis in sun-exposed areas Diarrhea Dementia	Symmetric hyper pigmented rash, similar in color and distribution to a sunburn, which is present in the exposed areas of skin	Niacin status can be assessed by measuring urinary N-methylnicotinamide or by measuring the erythrocyte NAD/NADP (ratio).
Chronic eczema (atopic dermatitis)	It is a chronic pruritic inflammatory skin disease that occurs most frequently in children but also affects adults. A family history of atopy (eczema, asthma, or allergic rhinitis) History of dermatitis involving the skin creases Personal or family history of asthma or hay fever	Symptoms beginning in a child before the age of 2 years or, in children <4 years, dermatitis affecting the cheeks or dorsal aspect of extremities. Dry skin and severe pruritus that is associated with cutaneous hyperreactivity to various environmental stimuli including exposure to food and inhalant allergens, irritants, and infection.	Visible dermatitis involving flexural surfaces. Presence of generally dry skin within the past year Erythema, papulation, oozing and crusting, excoriation.	Raised IgE or an eosinophilia Radioallergosorbent Test: blood is mixed separately with many different allergens and the antibody levels measured. High levels of antibodies in the blood signify an allergy to that substance Skin biopsy: a procedure that removes a small piece of the affected skin and sent for microscopic examination in a pathology laboratory.

Differentiating glucagonoma from other causes of hyperglycemia:

Glucagonoma can be differentiated from other causes of hyperglycemia which include:

• Type 2 DM
• MODY-DM
• Psychogenic polydipsia
• Diabetes insipidus
• Transient hyperglycemia
• Steroid therapy
• Renal tubular acidosis type-1
• Glucagonoma
• Cushing's syndrome
• Hypothyroidism
• Wolfram syndrome
• Alstrom syndrome

Disease	History and symptoms					Laboratory findings								Additional findings
	Polyuria	Polydipsia	Polyphagia	Weight loss	Weight gain	Serum glucose	Urinary Glucose	Urine PH	Serum Sodium	Urinary Glucose	24 hrs cortisol level	C-peptide level	Serum glucagon
Type 1 Diabetes mellitus	✔	✔	✔	✔	-	↑	↑	Normal	Normal	N/↑	Normal	↓	Normal	Auto antibodies present (Anti GAD-65 and anti insulin anti bodies)
Type 2 Diabetes mellitus	✔	✔	✔	✔	-	↑	↑	Normal	Normal	↑	Normal	Normal	↑	Acanthosis nigricans
MODY	✔	✔	✔	-	✔	↑	↑	Normal	Normal	↑	Normal	Normal	N	-
Psychogenic polydipsia	✔	✔	-	-	-	Normal	Normal	Normal	↓	Normal	Normal	Normal	Normal	-
Diabetes insipidus	✔	✔	-	-	-	Normal	Normal	Normal	↑	Normal	Normal	Normal	Normal	-
Transient hyperglycemia	-	-	-	-	-	↑	↑	Normal	Normal	↑	Normal	Normal	N/↑	In hospitalized patients especially in ICU and CCU
Steroid therapy	✔	-	-	-	✔	↑	↑	Normal	Normal	↑	↑	N/↑	N/↑	Acanthosis nigricans,
RTA 1	-	-	-	✔	-	Normal	Normal	↑	Normal	↑	Normal	Normal	Normal	Hypokalemia, nephrolithiasis
Glucagonoma	-	-	-	-	-	↑	Normal	Normal	Normal	-	Normal	Normal	↑	Necrolytic migratory erythema
Cushing syndrome	-	-	-	-	✔	↑	-	Normal	↓	N/↑	↑	Normal	Normal	Moon face, obesity, buffalo hump, easy bruisibility