Hypoproteinaemia

Hypoproteinaemia is a serum total protein concentration below the reference range (about 60 g/L). Because albumin forms about 60 percent of total protein, low total protein is usually due to low albumin, but low globulins (immunoglobulin deficiency) can also lower it, and the pattern directs the investigation.

• Low albumin and normal or low globulin: malnutrition and protein energy malnutrition (kwashiorkor in children), chronic liver disease, nephrotic syndrome, protein losing enteropathy, burns, severe inflammation or sepsis, haemodilution (pregnancy, overhydration, heart failure, intravenous fluids), and malabsorption.
• Low globulin (with normal albumin): primary or secondary hypogammaglobulinaemia (common variable immunodeficiency, X-linked agammaglobulinaemia, chronic lymphocytic leukaemia, myeloma with light chain only disease, nephrotic loss of immunoglobulin, protein losing enteropathy, immunosuppressive drugs, rituximab, and HIV in children).
• Artefactual: a drip arm sample (dilution), hypervolaemia, and posture (lower values when lying down).
• Hypoproteinaemia in children, pregnancy, and malnutrition is common in low resource settings.

• Oedema (generalised, pitting, periorbital), ascites, pleural and pericardial effusions, weight gain or loss, fatigue, muscle wasting, thin hair, skin changes (flaky paint dermatitis in kwashiorkor), poor wound healing, and recurrent infections in hypogammaglobulinaemia.
• Features of the cause: jaundice, spider naevi (liver), foamy urine, hypertension (nephrotic), chronic diarrhoea, steatorrhoea, weight loss (enteropathy, malabsorption), fever (inflammation), recurrent sinopulmonary infections (immune deficiency), and heart failure signs.
• Children with kwashiorkor: oedema, irritability, apathy, hair colour change, enlarged fatty liver, skin lesions, and infection.
• History: diet and food security, alcohol, drugs (steroids, immunosuppressants), HIV, hepatitis and TB risk, surgery or burns.
• Red flags: gross oedema with hypotension, severe diarrhoea, nephrotic range proteinuria, recurrent severe infections, or signs of liver failure.

• Measure albumin and total protein separately and calculate the globulin fraction; look for the combination.
• Urine dipstick and urine protein creatinine ratio (nephrotic syndrome when over 300 mg/mmol), urine microscopy, and 24 hour protein if needed.
• Liver function, INR, abdominal ultrasound; renal function, lipids, glucose; FBC, ESR, CRP; HIV, hepatitis B and C; thyroid function.
• Nutritional assessment: dietary history, body mass index, mid-upper arm circumference, weight-for-height in children, micronutrients, and vitamin levels.
• Gastrointestinal protein loss: faecal alpha-1 antitrypsin, faecal calprotectin, coeliac serology, stool tests for infections and parasites, endoscopy, and imaging.
• Immunoglobulins (IgG, IgA, IgM), serum protein electrophoresis, serum free light chains, and specific antibody responses to vaccines for suspected hypogammaglobulinaemia.
• Echocardiogram and chest X-ray for heart failure and effusions.
• Renal biopsy for suspected glomerular disease; liver biopsy or elastography when the cause is unclear.
• Differentials: dilutional hypoproteinaemia, nephrotic syndrome, cirrhosis, protein losing enteropathy, malnutrition, hypogammaglobulinaemia, and sampling artefact.

Treat the cause

• Nephrotic syndrome: furosemide 40 to 80 mg orally daily for oedema, ACE inhibitor (ramipril 2.5 to 10 mg daily), salt restriction, statin, anticoagulation if albumin is under 20 to 25 g/L with additional risk, and specialist immunosuppression according to the biopsy.
• Cirrhosis: alcohol abstinence, sodium restriction, spironolactone 100 to 400 mg with furosemide 40 to 160 mg daily for ascites, nutritional support with a late evening snack, treat the cause (hepatitis antivirals), and screening for varices.
• Protein losing enteropathy: treat inflammatory bowel disease, coeliac disease (gluten free diet), infection, or heart failure; low fat, medium chain triglyceride diet in intestinal lymphangiectasia.
• Hypogammaglobulinaemia: immunoglobulin replacement (intravenous 0.4 to 0.6 g/kg every 3 to 4 weeks, or subcutaneous weekly) for recurrent infections with low IgG; prophylactic antibiotics (azithromycin 250 mg three times weekly, or co-trimoxazole 960 mg daily) in selected patients; treat the cause (rituximab effect, myeloma).
• Heart failure, sepsis, and burns: treat the primary condition.

Nutritional rehabilitation

• Adults: high protein, high energy diet (protein 1.2 to 1.5 g/kg/day, energy 30 to 35 kcal/kg/day), oral nutritional supplements, micronutrient replacement (zinc 20 mg daily, multivitamin), and enteral or parenteral nutrition if needed; refeeding precautions with thiamine 100 mg daily and monitoring of phosphate, potassium, and magnesium.
• Children with kwashiorkor and severe acute malnutrition: stabilise (treat hypoglycaemia, hypothermia, dehydration cautiously with ReSoMal 5 mL/kg every 30 minutes for 2 hours then 5 to 10 mL/kg/h, correct electrolytes), antibiotics (amoxicillin 40 mg/kg twice daily for 5 days), vitamin A, folic acid 5 mg, zinc 2 mg/kg/day, then ready-to-use therapeutic food 150 to 220 kcal/kg/day for rehabilitation, with F-75 (stabilisation) then F-100 (rehabilitation) formulas in inpatient care.
• Treat infections including HIV, TB, and parasites (albendazole 400 mg single dose after stabilisation).

Albumin infusions (selected situations only)

• Large volume paracentesis (over 5 litres): 20 percent albumin 8 g per litre removed; spontaneous bacterial peritonitis and hepatorenal syndrome: dose set by the specialist; symptomatic hypovolaemia with refractory nephrotic oedema: 20 percent albumin with diuretic.
• Do not give albumin routinely for nutrition or to correct the number.

Monitoring and follow up

• Weigh and measure oedema daily in inpatients; repeat total protein and albumin every 1 to 4 weeks until stable; review diet, urine protein and liver function; refer to nephrology, hepatology, gastroenterology, or immunology according to the cause.