Carol Blenning, MD

Evidence summary

The evidence linking nail changes with nutritional deficiencies and toxic exposures is sparse, dated, and of low quality. Conditions associated with nail changes include iron deficiency, B₁₂ deficiency, hypoalbuminemia, protein malnutrition, and PCB/PCDF exposures.

Iron deficiency is associated with koilonychia
A case-control study of 400 infants in a low-income well-baby clinic found 22 with koilonychia, a prevalence of approximately 5%. Randomly selected age-matched infants without koilonychia served as controls.

Infants with koilonychia had significantly lower hematocrit (30% vs 34%; P<.005), hemoglobin (9.4 vs 10.7 g/dL; P<.02), and serum iron (50 vs 84 mcg/dL; P<.001) than controls.¹

B₁₂ deficiency can discolor nails, but changes are reversible
Four articles describe 5 case reports of pigment changes to nails associated with B₁₂ deficiency, all of which resolved with B₁₂ therapy. Nail changes included brownish reticulate pigmentation,² longitudinal hyperpigmented streaks,³ bluish-black pigment of all nails with transverse longitudinal hyperpigmented streaks,⁴ and entirely blue nails.⁵ B₁₂ levels ranged from undetectable to 113 pg/mL.

Hypoalbuminemia linked to Muehrcke’s lines
A cross-sectional study of 72 patients selected on the basis of general cachectic appearance found 44 to have low serum albumin. Of those, 10 (23%) had Muehrcke’s lines. All of the patients with Muehreke’s lines had albumin levels <2.7 g/dL. None of the 28 patients with normal albumin had Muehrcke’s lines.⁶

Kwashiorkor can cause fingernail clubbing
In a cross-sectional study of 60 children 1 to 4 years of age diagnosed with kwashiorkor without evidence of tuberculosis infection, fingernail clubbing was found in 46 (76.7%). Clubbing was mild in 26 (43.3%) children, moderate in 19 (37.7%), and severe in one (1.7%).⁷ Kwashiorkor is extremely rare in children in the United States and other developed countries.

Transplacental chemical exposures found to deform and discolor nails
A case-control study compared finger- and toenail findings from more than 100 Taiwanese children exposed transplacentally to high levels of PCBs and PCDFs with nail findings from a comparable number of controls. The investigators looked at parental reports and physical examination results.⁸

Although the rates of nail abnormalities reported by parents of exposed children differed slightly from rates documented by physical examination, children exposed to PCBs and PCDFs had consistently higher rates of nail deformity than controls. The researchers examined 117 cases and 106 controls. They identified dystrophic fingernails in 15% of exposed children and 1% of controls (odds ratio [OR]=15.4; 95% confidence interval [CI], 2-119); dystrophic toenails occurred in 32% of exposed children and 18% of controls (OR=2.2; 95% CI, 1.2-4.1). The most common fingernail deformities were grooves and ridges. The most common toenail deformities were koilonychias, ridges, thickening, and pigmentation changes.⁸

PCB exposure is an issue in the United States and other developed countries, but at much lower levels than the accidental contamination. Whether lower levels of exposure cause nail changes isn’t known.

Recommendations

No recommendations are available. A dermatology textbook lists several nail changes associated with nutritional deficiencies and toxic exposures (TABLE).⁹

Table
Nail changes linked to nutrition deficits and toxins⁹

Evidence summary

The evidence linking nail changes with nutritional deficiencies and toxic exposures is sparse, dated, and of low quality. Conditions associated with nail changes include iron deficiency, B₁₂ deficiency, hypoalbuminemia, protein malnutrition, and PCB/PCDF exposures.

Iron deficiency is associated with koilonychia
A case-control study of 400 infants in a low-income well-baby clinic found 22 with koilonychia, a prevalence of approximately 5%. Randomly selected age-matched infants without koilonychia served as controls.

Infants with koilonychia had significantly lower hematocrit (30% vs 34%; P<.005), hemoglobin (9.4 vs 10.7 g/dL; P<.02), and serum iron (50 vs 84 mcg/dL; P<.001) than controls.¹

B₁₂ deficiency can discolor nails, but changes are reversible
Four articles describe 5 case reports of pigment changes to nails associated with B₁₂ deficiency, all of which resolved with B₁₂ therapy. Nail changes included brownish reticulate pigmentation,² longitudinal hyperpigmented streaks,³ bluish-black pigment of all nails with transverse longitudinal hyperpigmented streaks,⁴ and entirely blue nails.⁵ B₁₂ levels ranged from undetectable to 113 pg/mL.

Hypoalbuminemia linked to Muehrcke’s lines
A cross-sectional study of 72 patients selected on the basis of general cachectic appearance found 44 to have low serum albumin. Of those, 10 (23%) had Muehrcke’s lines. All of the patients with Muehreke’s lines had albumin levels <2.7 g/dL. None of the 28 patients with normal albumin had Muehrcke’s lines.⁶

Kwashiorkor can cause fingernail clubbing
In a cross-sectional study of 60 children 1 to 4 years of age diagnosed with kwashiorkor without evidence of tuberculosis infection, fingernail clubbing was found in 46 (76.7%). Clubbing was mild in 26 (43.3%) children, moderate in 19 (37.7%), and severe in one (1.7%).⁷ Kwashiorkor is extremely rare in children in the United States and other developed countries.

Transplacental chemical exposures found to deform and discolor nails
A case-control study compared finger- and toenail findings from more than 100 Taiwanese children exposed transplacentally to high levels of PCBs and PCDFs with nail findings from a comparable number of controls. The investigators looked at parental reports and physical examination results.⁸

Although the rates of nail abnormalities reported by parents of exposed children differed slightly from rates documented by physical examination, children exposed to PCBs and PCDFs had consistently higher rates of nail deformity than controls. The researchers examined 117 cases and 106 controls. They identified dystrophic fingernails in 15% of exposed children and 1% of controls (odds ratio [OR]=15.4; 95% confidence interval [CI], 2-119); dystrophic toenails occurred in 32% of exposed children and 18% of controls (OR=2.2; 95% CI, 1.2-4.1). The most common fingernail deformities were grooves and ridges. The most common toenail deformities were koilonychias, ridges, thickening, and pigmentation changes.⁸

PCB exposure is an issue in the United States and other developed countries, but at much lower levels than the accidental contamination. Whether lower levels of exposure cause nail changes isn’t known.

Recommendations

No recommendations are available. A dermatology textbook lists several nail changes associated with nutritional deficiencies and toxic exposures (TABLE).⁹

Table
Nail changes linked to nutrition deficits and toxins⁹

Evidence summary

The evidence linking nail changes with nutritional deficiencies and toxic exposures is sparse, dated, and of low quality. Conditions associated with nail changes include iron deficiency, B₁₂ deficiency, hypoalbuminemia, protein malnutrition, and PCB/PCDF exposures.

Iron deficiency is associated with koilonychia
A case-control study of 400 infants in a low-income well-baby clinic found 22 with koilonychia, a prevalence of approximately 5%. Randomly selected age-matched infants without koilonychia served as controls.

Infants with koilonychia had significantly lower hematocrit (30% vs 34%; P<.005), hemoglobin (9.4 vs 10.7 g/dL; P<.02), and serum iron (50 vs 84 mcg/dL; P<.001) than controls.¹

B₁₂ deficiency can discolor nails, but changes are reversible
Four articles describe 5 case reports of pigment changes to nails associated with B₁₂ deficiency, all of which resolved with B₁₂ therapy. Nail changes included brownish reticulate pigmentation,² longitudinal hyperpigmented streaks,³ bluish-black pigment of all nails with transverse longitudinal hyperpigmented streaks,⁴ and entirely blue nails.⁵ B₁₂ levels ranged from undetectable to 113 pg/mL.

Hypoalbuminemia linked to Muehrcke’s lines
A cross-sectional study of 72 patients selected on the basis of general cachectic appearance found 44 to have low serum albumin. Of those, 10 (23%) had Muehrcke’s lines. All of the patients with Muehreke’s lines had albumin levels <2.7 g/dL. None of the 28 patients with normal albumin had Muehrcke’s lines.⁶

Kwashiorkor can cause fingernail clubbing
In a cross-sectional study of 60 children 1 to 4 years of age diagnosed with kwashiorkor without evidence of tuberculosis infection, fingernail clubbing was found in 46 (76.7%). Clubbing was mild in 26 (43.3%) children, moderate in 19 (37.7%), and severe in one (1.7%).⁷ Kwashiorkor is extremely rare in children in the United States and other developed countries.

Transplacental chemical exposures found to deform and discolor nails
A case-control study compared finger- and toenail findings from more than 100 Taiwanese children exposed transplacentally to high levels of PCBs and PCDFs with nail findings from a comparable number of controls. The investigators looked at parental reports and physical examination results.⁸

Although the rates of nail abnormalities reported by parents of exposed children differed slightly from rates documented by physical examination, children exposed to PCBs and PCDFs had consistently higher rates of nail deformity than controls. The researchers examined 117 cases and 106 controls. They identified dystrophic fingernails in 15% of exposed children and 1% of controls (odds ratio [OR]=15.4; 95% confidence interval [CI], 2-119); dystrophic toenails occurred in 32% of exposed children and 18% of controls (OR=2.2; 95% CI, 1.2-4.1). The most common fingernail deformities were grooves and ridges. The most common toenail deformities were koilonychias, ridges, thickening, and pigmentation changes.⁸

PCB exposure is an issue in the United States and other developed countries, but at much lower levels than the accidental contamination. Whether lower levels of exposure cause nail changes isn’t known.

Recommendations

No recommendations are available. A dermatology textbook lists several nail changes associated with nutritional deficiencies and toxic exposures (TABLE).⁹

Table
Nail changes linked to nutrition deficits and toxins⁹

Evidence Summary

Our comprehensive literature search found no studies that provide direct evidence for or against continuing to monitor microalbuminuria among patients with diabetes already on ACE inhibitor or ARB therapy. We reviewed and included indirect evidence and expert opinion to answer this clinical question.

Diabetes mellitus is the leading cause of end-stage renal disease in the Western world.¹ The prevalence of diabetic nephropathy continues to rise along with the rapidly rising prevalence of obesity and diabetes, with 40% of patients with diabetes at risk of developing nephropathy. One study that followed 5097 patients with type 2 diabetes over a median of 10.4 years found that 2% of patients progressed from normal levels of urinary protein to microalbuminuria; 2.8% changed from microalbuminuria to macroalbuminuria (urine albumin >300 mg in a 24-hour period); and 2.3% progressed to chronic renal disease (creatinine ≥2 mg/dL) from macroalbuminuria per year.² Chronic renal disease is more likely to occur in those patients whose hypertension or hyperglycemia is poorly controlled.

For patients with diabetes who develop microalbuminuria, the evidence is good for starting ACE inhibitors or ARBs for renal protection.^3,4 The American Diabetes Association (ADA) also recommends that patients with diabetes and hypertension and those aged >55 years with other cardiovascular risk factors (history of cardiovascular disease, dyslipidemia, or tobacco use) be started on ACE inhibitors or ARBs.¹ There is also good evidence that screening for microalbuminuria can identify those who might benefit from treatments that delay the onset of nephropathy.⁵

Recent studies have raised the possibility of further benefit in prevention and treatment of diabetic nephropathy by maximizing doses of ACE inhibitors or ARBs, and even from the dual blockade attained from using both. For example, during a 2-year trial—in which 590 patients with diabetes and microalbuminuria were randomized to receive placebo, 150 mg irbesartan, or 300 mg irbesartan—14.9% of the placebo group, 9.7% of the 150-mg group, and only 5.2% of the 300-mg group progressed to overt nephropathy.⁶ In very small randomized trial of 20 patients with type 2 diabetes, adding 16 mg of candesartan to the maximal dose of an ACE inhibitor decreased albuminuria an additional 28%.⁷

Experts argue that it may benefit patients to continue regular surveillance for the presence or progression of microalbuminuria even if they are already taking an ACE inhibitor or ARB so that therapy can be maximized.^1,8 However, no direct evidence supports this recommendation.

Recommendations from others

The ADA suggests that clinicians perform a test each year for microalbuminuria among patients with type 1 diabetes of ≥5 years duration, and in all patients with type 2 diabetes at diagnosis and during pregnancy. They also recommend continued surveillance of proteinuria to assess both response to therapy and progression of disease.¹

The National Kidney Foundation recommends continued surveillance of microalbuminuria to assess progression of chronic kidney disease and response to therapy.⁸

Evidence Summary

Our comprehensive literature search found no studies that provide direct evidence for or against continuing to monitor microalbuminuria among patients with diabetes already on ACE inhibitor or ARB therapy. We reviewed and included indirect evidence and expert opinion to answer this clinical question.

Diabetes mellitus is the leading cause of end-stage renal disease in the Western world.¹ The prevalence of diabetic nephropathy continues to rise along with the rapidly rising prevalence of obesity and diabetes, with 40% of patients with diabetes at risk of developing nephropathy. One study that followed 5097 patients with type 2 diabetes over a median of 10.4 years found that 2% of patients progressed from normal levels of urinary protein to microalbuminuria; 2.8% changed from microalbuminuria to macroalbuminuria (urine albumin >300 mg in a 24-hour period); and 2.3% progressed to chronic renal disease (creatinine ≥2 mg/dL) from macroalbuminuria per year.² Chronic renal disease is more likely to occur in those patients whose hypertension or hyperglycemia is poorly controlled.

For patients with diabetes who develop microalbuminuria, the evidence is good for starting ACE inhibitors or ARBs for renal protection.^3,4 The American Diabetes Association (ADA) also recommends that patients with diabetes and hypertension and those aged >55 years with other cardiovascular risk factors (history of cardiovascular disease, dyslipidemia, or tobacco use) be started on ACE inhibitors or ARBs.¹ There is also good evidence that screening for microalbuminuria can identify those who might benefit from treatments that delay the onset of nephropathy.⁵

Recent studies have raised the possibility of further benefit in prevention and treatment of diabetic nephropathy by maximizing doses of ACE inhibitors or ARBs, and even from the dual blockade attained from using both. For example, during a 2-year trial—in which 590 patients with diabetes and microalbuminuria were randomized to receive placebo, 150 mg irbesartan, or 300 mg irbesartan—14.9% of the placebo group, 9.7% of the 150-mg group, and only 5.2% of the 300-mg group progressed to overt nephropathy.⁶ In very small randomized trial of 20 patients with type 2 diabetes, adding 16 mg of candesartan to the maximal dose of an ACE inhibitor decreased albuminuria an additional 28%.⁷

Experts argue that it may benefit patients to continue regular surveillance for the presence or progression of microalbuminuria even if they are already taking an ACE inhibitor or ARB so that therapy can be maximized.^1,8 However, no direct evidence supports this recommendation.

Recommendations from others

The ADA suggests that clinicians perform a test each year for microalbuminuria among patients with type 1 diabetes of ≥5 years duration, and in all patients with type 2 diabetes at diagnosis and during pregnancy. They also recommend continued surveillance of proteinuria to assess both response to therapy and progression of disease.¹

The National Kidney Foundation recommends continued surveillance of microalbuminuria to assess progression of chronic kidney disease and response to therapy.⁸

Evidence Summary

Our comprehensive literature search found no studies that provide direct evidence for or against continuing to monitor microalbuminuria among patients with diabetes already on ACE inhibitor or ARB therapy. We reviewed and included indirect evidence and expert opinion to answer this clinical question.

Diabetes mellitus is the leading cause of end-stage renal disease in the Western world.¹ The prevalence of diabetic nephropathy continues to rise along with the rapidly rising prevalence of obesity and diabetes, with 40% of patients with diabetes at risk of developing nephropathy. One study that followed 5097 patients with type 2 diabetes over a median of 10.4 years found that 2% of patients progressed from normal levels of urinary protein to microalbuminuria; 2.8% changed from microalbuminuria to macroalbuminuria (urine albumin >300 mg in a 24-hour period); and 2.3% progressed to chronic renal disease (creatinine ≥2 mg/dL) from macroalbuminuria per year.² Chronic renal disease is more likely to occur in those patients whose hypertension or hyperglycemia is poorly controlled.

For patients with diabetes who develop microalbuminuria, the evidence is good for starting ACE inhibitors or ARBs for renal protection.^3,4 The American Diabetes Association (ADA) also recommends that patients with diabetes and hypertension and those aged >55 years with other cardiovascular risk factors (history of cardiovascular disease, dyslipidemia, or tobacco use) be started on ACE inhibitors or ARBs.¹ There is also good evidence that screening for microalbuminuria can identify those who might benefit from treatments that delay the onset of nephropathy.⁵

Recent studies have raised the possibility of further benefit in prevention and treatment of diabetic nephropathy by maximizing doses of ACE inhibitors or ARBs, and even from the dual blockade attained from using both. For example, during a 2-year trial—in which 590 patients with diabetes and microalbuminuria were randomized to receive placebo, 150 mg irbesartan, or 300 mg irbesartan—14.9% of the placebo group, 9.7% of the 150-mg group, and only 5.2% of the 300-mg group progressed to overt nephropathy.⁶ In very small randomized trial of 20 patients with type 2 diabetes, adding 16 mg of candesartan to the maximal dose of an ACE inhibitor decreased albuminuria an additional 28%.⁷

Experts argue that it may benefit patients to continue regular surveillance for the presence or progression of microalbuminuria even if they are already taking an ACE inhibitor or ARB so that therapy can be maximized.^1,8 However, no direct evidence supports this recommendation.

Recommendations from others

The ADA suggests that clinicians perform a test each year for microalbuminuria among patients with type 1 diabetes of ≥5 years duration, and in all patients with type 2 diabetes at diagnosis and during pregnancy. They also recommend continued surveillance of proteinuria to assess both response to therapy and progression of disease.¹

The National Kidney Foundation recommends continued surveillance of microalbuminuria to assess progression of chronic kidney disease and response to therapy.⁸