Can the elevation of AST and ALT in my patient with rhabdomyolysis be related to the muscle injury itself?

Yes! Elevated serum AST and ALT in the setting of rhabdomyolysis is not uncommon and, at least in some cases, appears to be related to the skeletal muscle injury itself.1,2

In a study of 16 patients considered to have significant muscle necrosis due to extreme exercise, polymyositis or seizures without evidence of liver disease (eg, viral hepatitis, exposure to hepatotoxic drugs, heart failure, biliary tract disease, recent hypotension) AST and, to lesser degree, ALT was elevated. For extreme exercise, the median AST and ALT concentrations were 2,466 IU/L and 497 U/L, respectively, while for seizures these levels were 1,448 U/L and 383 U/L respectively.1  

Another study reported AST elevation (>40 U/L) in 93.1% of patients with rhabdomyolysis and ALT elevation (>40 U/L) in 75.0% of patients with serum creatine kinase ≥1000 U/L. Further supporting a skeletal muscle origin for AST elevation was the finding that AST concentrations fell in parallel with CK drop during the first 6 days of hospitalization for rhabdomyolysis. It was posited that ALT concentrations dropped slower because of its longer serum half-life (47 hours vs 17 hours for AST).2 Despite these findings, concurrent liver injury as an additional source of AST or ALT elevation cannot be excluded.

Elevation of AST and ALT with muscle injury should not come as a surprise. AST is found in heart and skeletal muscle among many other organs. Even ALT which is considered more specific to liver is found in organs such as skeletal muscle, heart and kidney, though at lower concentrations.3

Bonus Pearl: Did you know that the first description of rhabdomyolysis in the literature involved English victims of crush injuries during World War II?2

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References

  1. Nathwani RA, Pais S, Reynolds TB, et al. Serum alanine aminotransferase in skeletal muscle diseases. Hepatology 2005;41:380-82. https://www.ncbi.nlm.nih.gov/pubmed/15660433
  2. Weibrecht K, Dayno M, Darling C, et al. Liver aminotransferases are elevated with rhabdomyolysis in the absence of significant liver injury. J Med Toxicol 2010;6:294-300. https://link.springer.com/article/10.1007%2Fs13181-010-0075-9
  3. Giannini EG, Testa R, Savarino V. Liver enzyme alteration: a guidance for clinicians. CMAJ2005;172:367-79. Giannini EG, Testa R, Savarino V. Liver enzyme alteration: a guidance for clinicians. CMAJ 2005;172:367-79. https://www.ncbi.nlm.nih.gov/pubmed/15684121
Can the elevation of AST and ALT in my patient with rhabdomyolysis be related to the muscle injury itself?

My patient with rheumatoid arthritis might have been exposed to tuberculosis. Does immunosuppressive therapy affect the results of interferon gamma release assay (IGRA) testing for latent tuberculosis?

The weight of the evidence to date suggests that immunosuppressive therapy, including steroids, other oral immunosuppressants and anti-tumor-necrosis factor (TNF) agents, may negatively impact IGRA results.1

In some ways the finding of false-negative IGRA in the setting of immunosuppression is intuitive since many immunosuppressive agents are potent inhibitors of T cells and interferon-gamma response. 1,2 Despite this, the initial reports have been somewhat conflicting which makes a 2016 meta-analysis of the effect of immunosuppressive therapy on IGRA results in patient with autoimmune diseases (eg, rheumatoid arthritis, lupus, inflammatory bowel disease) particularly timely. 1

This meta-analysis found a significantly lower positive IGRA results among patients on immunosuppressive therapy ( O.R. 0.66, 95% C.I. 0.53-0.83). Breakdown by IGRA test showed a significant association between QuantiFERON-TB Gold In-Tube and lower positive results and a trend toward the same with T-SPOT though the latter did not reach statistical significance with fewer evaluable studies (O.R. 0.81, 95% C.I 0.6-1.1).   Breakdown by type of immunosuppressant showed significantly negative impact of corticossteroids, other oral immunosuppressants, and anti-TNF agents for all. Some studies have reported daily steroid doses as low as 7.5 mg-10 mg may adversely impact T-cell responsiveness in IGRA. 3,4

So, whenever possible, testing for latent TB should be performed before immunosuppressants are initiated.

Bonus Pearl: Did you know that an estimated one-third of the world’s population may have latent TB?

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References

  1. Wong SH, Gao Q, Tsoi KKF, et al. Effect of immunosuppressive therapy on interferon gamma release assay for latent tuberculosis screening in patients with autoimmune diseases: a systematic review and meta-analysis. Thorax 2016;71:64-72. https://thorax.bmj.com/content/thoraxjnl/71/1/64.full.pdf
  2. Sester U, Wilkens H, van Bentum K, et al. Impaired detection of Mycobacterium tuberculosis immunity in patents using high levels of immunosuppressive drugs. Eur Respir J 2009;34:702-10. https://erj.ersjournals.com/content/34/3/702
  3. Kleinert S, Kurzai O, Elias J, et al. Comparison of two interferon-gamma release assays and tuberculin skin test for detecting latent tuberculosis in patients with immune-mediated inflammatory diseases. Ann Rheum Dis 2010;69:782-4. https://ard.bmj.com/content/69/4/782
  4. Ponce de Leon D, Acevedo-Vasquez E, Alvizuri S, et al. Comparison of an interferon-gamma assay with tuberculin skin testing for detection of tuberculosis (TB) infection in patients with rheumatoid arthritis in a TB-endemic population. J Rheumatol 2008;35:776-81. https://www.ncbi.nlm.nih.gov/pubmed/18398944
My patient with rheumatoid arthritis might have been exposed to tuberculosis. Does immunosuppressive therapy affect the results of interferon gamma release assay (IGRA) testing for latent tuberculosis?

What’s causing an isolated GGT elevation in my patient with an abnormal alkaline phosphatase on her routine admission lab?

Although serum gamma-glutamyl transpeptidase or GGT is a very sensitive test for liver disease, especially of biliary origin, it’s by no means a very specific test. Besides the liver, GGT is found in the kidneys, pancreas, prostate, heart, brain, and seminal vesicles but not in bone (1-4).

 
Obesity, alcohol consumption and drugs are common causes of GGT elevation (2). As early as 1960s, elevated GGT was reported in such seemingly disparate conditions as diabetes mellitus, congestive heart failure, myocardial infarction, nephrotic syndrome and renal neoplasm (3). Nonalcoholic steatohepatitis, viral hepatitis, biliary obstruction, COPD, liver metastasis, drug-induced liver injury can all cause GGT elevation (1-4).

 
An isolated GGT does not necessarily indicate serious or progressive liver disease. That’s one reason it’s often not included in routine “liver panel” lab tests (1).

What to do when GGT is high but other liver panel tests such as ALT, AST, albumin, and bilirubin are normal? If your patient is at risk of acquired liver disease, then further workup may be necessary (eg, hepatitis B and C screening tests). Alcohol consumption should be queried. Don’t forget conditions associated with iron overload. If your patient is obese, diabetic or has elevated both lipids, an ultrasound of the liver to look for fatty liver should be considered. In the absence of risk factors, symptoms, or physical exam suggestive of liver disease, isolated GGT elevation should not require further investigation (1).

 
One good thing that may come out of finding an isolated elevated GGT is to encourage your patient to curb alcohol consumption or lose weight when indicated. But don’t rely on a normal GGT to rule out heavy alcohol consumption as it may miss 70% to 80% of cases (6)! 

 
Bonus Pearl: Did you know that GGT activity is thought to increase in alcohol use due to its role in maintaining intracellular glutathione, an anti-oxidant, at adequate levels to protect cells from oxidative stress caused by alcohol?

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References

1. Carey WD. How should a patient with an isolated GGT elevation be evaluated? Clev Clin J Med 2000;67:315-16. https://www.ncbi.nlm.nih.gov/pubmed/10832186
2. Newsome PN, Cramb R, Davison SM, et al. Guidelines on the management of abnormal liver blood tests. Gut 2018;67:6-19. https://gut.bmj.com/content/gutjnl/67/1/6.full.pdf
3. Whitfield JB, Pounder RE, Neale G, et al. Serum gamma-glutamyl transpeptidase activity in liver disease. Gut 1972;13:702-8. https://www.ncbi.nlm.nih.gov/pubmed/4404786
4. Tekin O, Uraldi C, Isik B, et al. Clinical importance of gamma glutamyltransferase in the Ankara-Pursaklar region of Turkey. Medscape General Medicine 2004;6(1):e16. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1140713/
5. Van Beek JHDA, de Moor MHM, Geels LM, et al. The association of alcohol intake with gamma-glutamyl transferase (GGT) levels:evidence for correlated genetic effects. Drug Alcohol Depend 2014;134:99-105. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3909645/

6. Bertholet N, Winter MR, Cheng DM, et al. How accurate are blood (or breath) tests for identifying self-reported heavy drinking among people with alcohol dependence? Alcohol and Alcoholism 2014;49:423-29. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4060735/pdf/agu016.pdf

What’s causing an isolated GGT elevation in my patient with an abnormal alkaline phosphatase on her routine admission lab?

What’s the connection between lemon juice and disseminated candidiasis in my patient with illicit IV drug use?

Lemon juice is often used by IV drug users to help dissolve poorly water soluble street drugs, such as brown heroin or crack-cocaine, and may serve as a vehicle for Candida albicans infection. 1-3

Contamination of lemon juice (either from wild lemons or from the plastic containers) is thought to occur from either the skin and/or oropharynx of the user.1  Other fruit juices such as orange juice as well as raspberry syrup have been implicated as a source of disseminated candidiasis in IV drug users.4

Experimental inoculation of lemons with small numbers of C. albicans has demonstrated rapid growth of the organism at room temperature resulting in inadvertent injection of a large inoculum size. 2 Once inoculated directly into the blood stream, C. albicans disseminates and can present in many ways, including skin lesions, ocular lesions/endophthalmitis, and osteoarticular infections (eg, costochondral, hip joint, and vertebral infections).1  

So it is advisable to not only ask about what recreational drug is being injected but also what it is injected with!

Bonus Pearl: Did you know that although lemon juice is an excellent growth medium for C. albicans, it has bactericidal properties against Staphylococcus aureus and Pseudomonas aeruginosa? 1

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References

  1. Bisbe J, Miro JM, Latorre X, et al. Disseminated candidiasis in addicts who use brown heroin: report of 83 cases and review. Clin Infect Dis 1992;15:910-23. https://www.ncbi.nlm.nih.gov/pubmed/1457662
  2. Newton-John HGF, Wise K, Looke DFM. Role of the lemon in disseminated candidiasis of heroin abusers. Med j Aust 1984;140:780-81. https://onlinelibrary.wiley.com/doi/abs/10.5694/j.1326-5377.1984.tb132597.x?sid=nlm%3Apubmed
  3. Shankland GS, Richardson MD. Source of infection in candida endophthalmitis in drug addicts. Br J Ophthalmol 1986;292:1106-7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1954783/pdf/702.pdf
  4. Scheidegger C, Pietrzak J, Frei R. Methadone diluted with contaminated orange juice or raspberry syrup as a potential source of disseminated candidiasis in drug abusers. Eur J Clin Microbiol Infect Dis 1993;12:229-31. https://link.springer.com/article/10.1007/BF01967124
What’s the connection between lemon juice and disseminated candidiasis in my patient with illicit IV drug use?

Is my patient with gout at higher risk of cancer?

Although the association of gout with cardiovascular disease, chronic kidney disease, hypertension, diabetes mellitus or obesity is well known, increasingly number of epidemiologic studies support the association of gout with higher risk of malignancy. 1,2

A 2015 meta-analysis of 3 studies involving over 50,000 persons concluded that gout was an independent risk factor for cancer, particularly urological, gastrointestinal and lung cancers. 1

A population-based study of comorbidities in over 2 million persons in Sweden found that in addition to an increased risk of diabetes mellitus, hypertension, chronic heart failure, chronic kidney disease and alcohol abuse, gout was associated with increased risk of malignancy: odds ratio 1.3 (1.2-1.5) in men and 1.1 (1.1-1.2) in women. 2

Although serum uric acid has been considered to have anti-oxidant properties, a prospective study of over 28,000 women followed over a median of 15.2 years did not find high serum acid levels to be protective of cancer.3 In fact, uric acid levels > 5.4 mg/dL at the time of subject enrollment was independently associated with increased risk of total cancer mortality and deaths from a variety of malignant neoplasms, including those of breast, female genital organs, and nervous systems. 3 In a similar prospective study involving men, high uric acid levels (>6.7 mg/dL) were associated with increased risk of mortality from gastrointestinal, respiratory and intrathoracic organ malignancies. 4

Whether the observed association between gout and higher risk of malignancy is causal or due to the company that gout often keeps (eg, lifestyle) is unclear.

Fun fact: Did you know that among mammals, only humans, great apes and certain breeds of dogs (eg, Dalmation) produce elevated levels of uric acid in the urine and blood? 5

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References

  1. Wang W, Xu D, Wang B, et al. Increased risk of cancer in relation to gout: a review of three prospective cohort studies with 50,358 subjects. Mediators of Inflammation 2015, Article ID 680853, 6 pages. https://www.ncbi.nlm.nih.gov/pubmed/26504360
  2. Wandell P. Gout and its comorbidities in the total population of Stockholm. Preventive Medicine 2015; 81:387-91. ISSN 0091-7435. https://www.ncbi.nlm.nih.gov/pubmed/26500085
  3. Strasak AM, Rapp K, Hilbe W, et al. The role of serum uric acid as an antioxidant protecting against cancer: prospective study in more than 28000 older Austrian women. Ann Onc 2007;18:1893-97. https://www.ncbi.nlm.nih.gov/pubmed/17785768
  4. Strasak Am, Hilbe RK, Oberaingner W, et al. Serum uric acid and risk of cancer mortality in a large prospective male cohort. Cancer Causes Control 2007;18:1021-9. https://www.ncbi.nlm.nih.gov/pubmed/17665312
  5. Bannasch D, Safra N, Young A, et al. Mutations in the SLC2A9 gene cause hyperuriosuria and hyperuricemia in the dog. PLOS Genet 2008;4:e1000246. https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1000246&type=printable
Is my patient with gout at higher risk of cancer?

Why is my patient with systemic amyloidosis at higher risk of bleeding?

The major mechanism of bleeding tendency in primary systemic amyloidosis (AL) appears to revolve around amyloid deposit infiltration of the vasculature and musculature, leading to amyloid angiopathy, fragility, impaired vasoconstriction, tears and hemorrhage. 1,2 Other potential mechanisms include:

  • Presence of plasma inhibitors of fibrinogen conversion to fibrin
  • Deficiencies of factor X, IX and V due to their affinity for amyloid substance
  • Presence of circulating heparin-like anticoagulants
  • Uremic platelet dysfunction in the presence of renal involvement

In a study involving 36 patients with AL, ~30% had bleeding symptoms with alterations of 1 or more clotting tests found in ~85%: prolonged prothrombin time (PT) ratio (22%), activated partial thromboplastin time (aPTT) (65%) and thrombin time (85%).

Clinical manifestations of amyloidosis related to its bleeding diathesis include petechiae, ecchymoses, purpura (“raccoon eyes when periorbital), uncontrollable epistaxis, gingival bleeding, and gastrointestinal bleed or submucosal hematomas. 1-6

Due to its convenience and relative safety, a biopsy of abdominal fat or minor salivary glands is often initially performed for definitive diagnosis of amyloidosis, followed by biopsy of specific organs (eg, kidney, liver), if needed. 3,6

Due to the potential risk of bleeding complications, transjugular liver biopsy is preferred over percutaneous approach. This is because the liver capsule is not perforated with transjugular liver biopsy and if bleeding occurs, the blood returns directly into the venous system rather than into the peritoneum. 7-8 

Bonus Pearl: Did you know that AL amyloidosis is the most common type of systemic amyloidosis in western countries? This is because the incidence of the other major type of amyloidosis (AA), often related to chronic infections or inflammatory diseases, has been dropping in these countries.3

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References

  1. Gamba G, Montani N, Anesi E, et al. Clotting alterations in primary systemic amyloidosis. Haematologica 2000;85:289-92. https://moh-it.pure.elsevier.com/en/publications/clotting-alterations-in-primary-systemic-amyloidosis
  2. Marconcini LAL, Stewart FM, Sonntag L, et al. AL amyloidosis complicated by persistent oral bleeding. Case Reports in Hematology 2015, Article ID 981346. https://www.hindawi.com/journals/crihem/2015/981346/
  3. Desport E, Bridoux F, Sirac C, et al. AL Amyloidosis. Orphanet Journal of Rare Diseases 2012, 7:54. https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-7-54
  4. Yoshii S, Mabe K, Nosho K, et al. Submucosal hematoma is a highly suggestive finding for amyloid light-chain amyloidosis: Two case reports. W J Gastroenterol 2012;4:434-37. https://www.ncbi.nlm.nih.gov/pubmed/23125904
  5. Kon T, Nakagawa N, Yoshikawa F, et al. Systemic immunoglobulin light-chain amyloidosis presenting hematochezia as the initial symptoms. Clin J Gastroenterol 2016;9:243. http://europepmc.org/article/med/27318996
  6. Petre S, Shah IA, Gilani N. Review article:gastrointestinal amyloidosis-clinical features, diagnosis and therapy. Alim Pharmacol Ther 2008;27:1006-16. https://www.ncbi.nlm.nih.gov/pubmed/18363891
  7. Grant A, Neuberger J. Guidelines on the use of liver biopsy in clinical practice. Gut 1999;45(Suppl IV):IV1-IV11. https://www.ncbi.nlm.nih.gov/pubmed/10485854
  8. Dohan A, Guerrache Y, Boudiaf M, et al. Transjugular liver biopsy: Indications, technique and results. Diagnostic and Interventional Imaging 2014;95:11-15. https://www.ncbi.nlm.nih.gov/pubmed/24007769
Why is my patient with systemic amyloidosis at higher risk of bleeding?

How long should I treat my patient with urinary tract infection and E. Coli bacteremia?

Although traditionally 7 to 14 days of antibiotic therapy has been recommended for Gram-negative bacteremia, more recent studies suggest that shorter antibiotic treatment courses are as effective as longer treatments for a variety of infections, particuarly those due to Enterobacteriaceae (eg, E. Coli, Klebsiella sp) in patients with low severity illness (1). 

Keep in mind that short course therapy may not apply to all patients with UTI and bacteremia, such as those with prostatitis (not included in the most recent study [1,2]), which requires longer course of antibiotics (3)

 
A 2019 randomized-controlled study involving primarily patients with bacteremia caused by E. Coli or Klebsiella sp. (~75%) with most cases associated with UTI (~70%) found that 7 days was as effective as 14 days of treatment in hemodynamically stable patients who are afebrile for at least 48 hours without an ongoing focus of infection (1). More specifically, there was no significant difference between the 2 groups in the rates of relapse of bacteremia or mortality at 14 or 28 days.

 
An accompanying editorial concluded that “7 days of treatment may be sufficient for hospitalized, non-critically ill patients with Gram-negative bacteremia and with signs of early response to treatment” (4)  Again, the accent should be on hemodynamically stable patients who respond rapidly to treatment. 

 
Bonus Pearl: While on the subject of shorter course antibiotic therapy, a 2016 “mantra” article nicely summarizes more recent suggestions for common infectious disease conditions (5). Obviously, clinical judgment should be exercised in all cases.
• Community-acquired pneumonia                               3-5 days (vs 7-10 days)
• Nosocomial pneumonia                                                 8 days or less (vs 10-15 days)
• Pyelonephritis                                                                  5-7 days (vs 10-14 days)
• Intraabdominal infection                                             4 days (vs 10 days)
• COPD acute exacerbation                                             5 days or less (vs >6 days)
• Acute bacterial sinusitis                                               5 days (vs 10 days)
• Cellulitis                                                                            5-6 days (vs 10 days)

 

 

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References
1. Yahav D, Franceschini E, Koppel F, et al. Seven versus 14 days of antibiotic therapy for uncomplicated Gram-negative bacteremia: A noninferiority randomized controlled trial. Clin Infect Dis 2019; 69:1091-8. https://academic.oup.com/cid/article/69/7/1091/5237874       2. Yahav D, Mussini C, Leibovici L, et al. Reply to “Should we treat bacteremic prostatitis for 7 days”.  Clin Infect Dis 2010;70:751-3. DOI:10:1093/cid/ciz393.

3.  De Greef J, Doyen L, Hnrard S, et al. Should we treat bacteremic prostatitis for 7 days? Clin Infect Dis 2020;70:351https://academic.oup.com/cid/article-abstract/70/2/351/5488067?redirectedFrom=fulltext
4. Daneman D, Fowler RA. Shortening antibiotic treatment durations for bacteremia. Clin Infect Dis 2019;69:1099-1100. https://academic.oup.com/cid/article-abstract/69/7/1099/5237877?redirectedFrom=fulltext
5. Spellberg B. The new antibiotic mantra: “ Shorter is better”. JAMA Intern Med 2016;176:1254-55. https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/2536180

How long should I treat my patient with urinary tract infection and E. Coli bacteremia?

Why is my diabetic patient complaining of arm pain and localized edema for couple of weeks without an obvious cause?

Aside from the usual suspects associated with a painful extremity (eg, trauma, deep venous thrombosis and soft tissue infections), think of spontaneous diabetic myonecrosis (DMN), also known as diabetic muscle infarction (1-3).

DMN is characterized by abrupt onset of painful swelling of the affected muscle, most often of the lower extremities, but also occasionally upper extremities. DMN occurs in patients with longstanding DM whose blood glucose control has deteriorated over time, often with nephropathy, retinopathy and/or neuropathy (1-3).

Couple of things to remember when considering DMN in your differential of a painful extremity. First, except for localized edema and tenderness over the involved muscle, the exam may be unremarkable. Specifically, there is no erythema or signs of compartment syndrome and fever is absent in the great majority of patients (~90%) (2). Even white blood cell count and creatine kinase (CK) are usually normal. The reason for normal CK at presentation is not clear but CK might have already peaked by the time of patient presentation (3). In contrast, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are usually elevated (>80%) (1).

MRI (without contrast in patients with renal insufficiency) is the imaging of choice with muscle enlargement and edema with hyperintense signal on T2-weighted images and other changes, including perifascial, perimuscular and or subcutaneous edema (1-3). Muscle biopsy is not currently recommended because of its adverse impact on time to symptomatic improvement. Non-surgical therapy, with rest, analgesia and glycemic control is usually recommended (1-3).

 
Though its exact cause is still unclear, atherosclerosis, diabetic microangiopathy, vasculitis with thrombosis and ischemia-reperfusion injury have been posited as potential precipitants for DMN. The role of anti-phospholipid syndrome, particularly in patients with type I DM, is unclear (1,2).

 
Bonus pearl: Did you know that symptoms of DMN may last for weeks with at least one-third of patients having a recurrence in the same muscle or elsewhere (1)?

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Reference
1. Horton WB, Taylor JS, Ragland TJ, et al. Diabetic muscle infarction: a systematic review. BMJ Open Diabetes Research and Care 2015;3:e000082.
2. Trujillo-Santos AJ. Diabetic muscle infarction. An underdiagnosed complication of long-standing diabetes. Diabetes Care 2003;26:211-15.
3. Diabetes muscle infarction in end-stage renal disease:A scoping review on epidemiology, diagnosis and treatment. World J Nephrol 2018;7:58-64.

Why is my diabetic patient complaining of arm pain and localized edema for couple of weeks without an obvious cause?

Could measurement of urinary albumin-protein ratio be useful in my patient with renal insufficiency and proteinuria?

A spot urine test for determination of albumin-protein ratio (uAPR) may be useful in distinguishing glomerular vs tubulointerstitial source of proteinuria. A low (<0.4) uAPR, defined as urinary albumin to creatinine ratio(uACR)/urinary protein to creatinine ratio (uAPR) is more suggestive of a tubulointerstitial renal disease and less suggestive of glomerular pathology.1-3  

A 2012 study involving simultaneous measurements of urinary albumin and total protein in over 1000 proteinuric patients found a relatively high (0.84) area under curve (AUC) in a receiver operating characteristic curve analysis for uAPR (vs 0.74 for uACR and 0.54 for uPCR) in discriminating between tubular and non-tubular proteinuria pattern on urine protein electrophoresis and immunofixation. An uAPR cut-off of <0.4 was found to be 88% sensitive and 99% specific for the diagnosis of primary tubulointerstitial disorders on renal biopsy.1  

Due to the limitations of this study (including a relatively small subset of patient who had renal biopsy), a related editorial concluded that a low uAPR gives a “reasonable prediction of a tubular electrophoretic proteinuria”, but that it warrants further validation. Nevertheless, uAPR could potentially be useful in patients with moderate proteinuria (>300 mg/day to <3 g/day) who have not had renal biopsy and  where assessment of likelihood of tubulointerstitial vs glomerular source of proteinuria is desired.3 Interestingly, the utility of uAPR in predicting non-glomerular source of hematuria has also been reported.4

Bonus pearl: Did you know that the negatively-charged glomerular capillary wall repels negatively charged albumin thus preventing its filtration (charge-barrier) (5)?  

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References

  1. Smith ER, Cai MMX, McMahon LP, et al. The value of simultaneous measurement of urinary albumin and total protein in proteinuric patients. Nephrol Dial Transplant 2012;27:1534-41. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4035283/
  2. Fraser SDS, Roderick PJ, McIntyre NJ, et al. Assessment of proteinuria in patients with chronic kidney disease stage 3: albuminuria and non-albumin proteinuria. PLOS ONE 2014;9:e98261. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4035283/pdf/pone.0098261.pdf
  3. Ellam T, Nahas ME. Urinary albumin to protein ratio: more of the same or making a difference. Nephrol Dial Transplant 2012;27:1293-96. https://www.ncbi.nlm.nih.gov/pubmed/22362784
  4. Ohisa N, Yoshida K, Matsuki R, et al. A comparison of urinary albumin-total protein ratio to phase-contrast microscopic examination of urine sediment for differentiating glomerular and nonglomerular bleeding. Am J Kidney Dis 2008;52:235-41. https://www.ajkd.org/article/S0272-6386(08)00828-7/pdf
  5. Venkat KK. Proteinuria and microalbuminuria in adults: significance, evaluation, and treatment. S Med J 2004;97:969-79. https://internal.medicine.ufl.edu/files/2012/07/5.18.05.04.-Proteinuria-review.pdf
Could measurement of urinary albumin-protein ratio be useful in my patient with renal insufficiency and proteinuria?

Can hypothyroidism be associated with hypertension?

Short answer: Yes! Just as hyperthyroidism, hypothyroidism is also associated with hypertension (1-5). Compared to normal subjects, patients with hypothyroidism have a 3-fold increased prevalence of hypertension, usually diastolic (2). In fact, hypothyroidism has been identified as a cause of hypertension in 3% of patients with high blood pressure and is the most common cause of secondary hypertension after renovascular hypertension (1-3).

 
High systemic vascular resistance and increased arterial stiffness are among the important mechanisms explaining hypothyroid-induced hypertension (1). High systemic vascular resistance is thought to be due to the absence of the vasodilator effects of T3 on vascular smooth muscle and decreased response to beta-adrenergic stimulation, which in turn leads to increased alpha-adrenergic responses. Increased arterial stiffness may also contribute due to the myxedema involvement of the arterial wall. Other potential factors include free water retention due to an inappropriate secretion of anti-diuretic hormone (ADH) and obesity in hypothyroid patients (1,4).

 
Similar to its prevalence in hypothyroidism, hypertension is about 3-fold higher in patients with overt hyperthyroidism compared to normal subjects (1). However, in contrast to hypothyroid patients, the hypertension in hyperthyroidism is primarily “cardiogenic”, where the increased blood pressure levels are mainly maintained by the increased cardiac output due to high stroke volume and heart rate (1).

 
Thus, both hypothyroidism and hyperthyroidism can be associated with hypertension!

 
Bonus pearl: Did you know that hypertension due to hypothyroidism is typically associated with a low-renin state, is particularly sensitive to salt intake, and may not respond as well to angiotensin -converting enzyme inhibitors (1)?

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References
1. Mazza A, Beltramello G, Armigliato M, et al. Arterial hypertension and thyroid disorders: what is important to know in clinical practice? Annales d’Endocrinologie 2011;72:296-303. https://www.sciencedirect.com/science/article/abs/pii/S0003426611000886
2. Dernellis J, Panaretou M. Effects of thyroid replacement therapy on arterial blood pressure in patients with hypertension and hypothyroidism 2002; Am Heart J 2002;143:718-24. https://www.ncbi.nlm.nih.gov/pubmed/11923811
3. Anderson GH, Blakeman N, Steeten DHP. The effect of age on prevalence of secondary forms of hypertension in 4429 consecutively referred patients. J Hypertension 1994;12:609-15. https://insights.ovid.com/hypertension/jhype/1994/05/000/effect-age-prevalence-secondary-forms-hypertension/15/00004872
4. Saito I, ITO K, Saruta T. Hypothyroidism as a cause of hypertension. Hypertension 1983;5:112-15. https://www.ahajournals.org/doi/10.1161/01.hyp.5.1.112
5. Chaker L, Bianco AC, Jonklaas J, et al. Hypothyroidism. Lancet 2017;390:1550-62. https://www.ncbi.nlm.nih.gov/pubmed/28336049

Can hypothyroidism be associated with hypertension?