Differential for Elevated Transaminases

Developing approaches to a relatively common lab abnormality is essential in any ambulatory setting. Isolated liver transaminase elevation has a broad differential and is perhaps best considered in 3 categories before being appropriately narrowed with clinical and laboratory investigations.

1) Common Causes:

- Non-Alcoholic Liver Disease

    Hx: Metabolic syndrome; Ix: Lipids, a1c elevated

- Alcoholic Liver Disease

   Hx: EtOH consumption; Ix: AST:ALT > 2

2) Uncommon Causes

- Medications

    Hx: consider overdose; Ix: plasma concentrations

- Hepatitis B

    Hx: vaccination, travel, high-risk behaviour; Ix: HBV serology

- Hepatitis C

    Hx: travel, high-risk behaviour; Ix: HCV serology

- Hereditary hemochromatosis

    Hx: Family history; Ix: Serum iron, ferritin

3) Rare Causes

Alpha-1-antitrypsin deficiency

    Hx: Early emphysema, family history; Ix: serum alpha-1-antitrypsin

Autoimmune hepatitis

    Hx: young women, autoimmune disorders; Ix: SPEP, ANA, smAb, liver/kidney microsome type1 Ab

Wilson disease

    Hx: neuropsychiatric, Kayser-Fleischer rings, Ix: Serum Ceruloplasmin

-TJ-

Reference:

Oh RC, Hustead TR, Ali SM, Pantsari MW. Mildly Elevated Liver Transaminase Levels: Causes and Evaluation. Am Fam Physician. 2017 Dec 1;96(11):709-715. PMID: 29431403.

Clinical Findings of Hypertrophic Cardiomyopathy

The pathophysiology of hypertrophic cardiomyopathy (HCM) consists of dynamic left ventricular outflow tract obstruction (LVOTO), mitral regurgitation (MR), diastolic dysfunction, myocardial ischemia, arrhythmias, and autonomic dysfunction. 

For a given patient with HCM, the clinical outcome may be dominated by one of these components or may be the result of a complex interplay. Thus, it is prudent to consider the potential presence of such abnormalities in a comprehensive clinical evaluation and address their impact in the management of these patients.

The classic HCM patient has 4 clinical findings: 

1) Dynamic crescendo-decrescendo systolic murmur

i. best heard over the lower left sternal border

ii. radiates to axilla (not carotids)

iii. more audible with increased contractility/preload

iv. less audible with decreased preload, increased systemic resistance

2) Prominent apical point of maximal impulse

i. shifted laterally

ii. either bifid or trifid

3) Abnormal carotid pulse

i. Carotid double pulsation (pulsus bisferiens)

4) Fourth heart sound (S4)

These clinical findings are sequelae of LVOTO. Septal hypertrophy leads to narrowing of the LVOT. Subsequent abnormal flow dynamically displaces the mitral leaflets anteriorly during systole, further exacerbating the LVOTO. Furthermore, the anatomy of the mitral valve is also altered which makes the valve susceptible to mitral regurgitation and systolic LVOTO.

-TJ-

Reference:

Ommen SR, Mital S, Burke MA, Day SM, Deswal A, Elliott P, Evanovich LL, Hung J, Joglar JA, Kantor P, Kimmelstiel C, Kittleson M, Link MS, Maron MS, Martinez MW, Miyake CY, Schaff HV, Semsarian C, Sorajja P. 2020 AHA/ACC Guideline for the Diagnosis and Treatment of Patients With Hypertrophic Cardiomyopathy: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2020 Dec 22;142(25):e558-e631. doi: 10.1161/CIR.0000000000000937. Epub 2020 Nov 20. Erratum in: Circulation. 2020 Dec 22;142(25):e633. PMID: 33215931.

Approach to Liver Chemistries

First of all - even the terminology is confusing. The American College of Gastroenterology now recommends using the terminology 'liver chemistries'. Historically, 'liver enzymes' referred to serum levels of ALT, AST, ALP (and GGT) while 'liver function tests' referred to PT/INR, conjugated (direct) bilirubin, albumin.

Liver enzymes abnormalities are typically the first indication of mild or chronic pathology. Clinical manifestations and abnormalities in PT/direct bili/albumin usually only occur in the context of acute or well-established disease.

Liver enzymes can be listed from most specific to least specific:

- ALT (hepatocytes only)

- AST (hepatocytes AND skeletal/cardiac muscle)

- ALP (hepatocytes lining bile canaliculi AND bone, placenta, GI tract)

- GGT can be used to confirm ALP elevations are specific to bile canaliculi disruption, however, it is even less specific than ALP so there is no clinical utility in ordering it without an established ALP elevation.

Building on this, there are 2 (ish) basic patterns of liver chemistries to recognize:

1.) Hepatotoxic*

- AST, ALT elevation predominate

(1a) Alcoholic liver disease

- AST:ALT > 2

(1b) Non-alcoholic liver disease

- AST:ALT < 1

2.) Obstructive

- ALP, direct bili elevations predominate

*Should ALT/AST >1000 or there be abnormalities in PT/INR, direct bilirubin, albumin consider acute/severe disease

-TJ-

Reference:

Kwo PY, Cohen SM, Lim JK. ACG Clinical Guideline: Evaluation of Abnormal Liver Chemistries. Am J Gastroenterol. 2017 Jan;112(1):18-35. doi: 10.1038/ajg.2016.517. Epub 2016 Dec 20. PMID: 27995906.

Secondary Prevention Counselling

During my outpatient cardiology clinic experience, a saw a 50-something year old gentleman who was being referred to the clinic for regular cardiology follow up after a posterior STEMI in 2011. He had not seen a cardiologist for four years, and mentioned poor medication adherence. This was a reminder for me to review the pharmacologic and non-pharmacologic secondary prevention strategies in patients with coronary artery disease:

Pharmacologic

1. Anticoagulation: aspirin 81mg tablet
2. Blood pressure control (<140/90 or <130/80 for patients with diabetes or chronic kidney disease): 
3. ACEi/ARB
4. Beta-blocker
5. Statin: goal of <2 or 50% reduction in LDL cholesterol

Non-pharmacologic

1. Smoking cessation
2. Weight management: 10% weight loss is recommended for overweight/obese patients 
3. Exercise-based cardiac rehabilitation and/or physical activity: 150 minutes per week of moderate-vigorous exercise is recommended
4. Diet: Portfolio and Mediterranean diets have proven benefits.
5. Influenza immunization

Together, we came up with realistic goals for this patient to achieve by his next visit. I emphasized the importance of goal-setting and taking small but permanent steps towards these lifestyle changes in a way that best suited his life. 

Resources: 

1. Secondary Prevention of Coronary Artery Disease. American Family Physician. https://www.aafp.org/afp/2010/0201/afp20100201p289.pdf

-IL-

Taking a history for secondary hypertension

During my General Internal Medicine outpatient clinic experience, many patients were being referred for hypertension. When working up a patient for hypertension, it is important to rule out secondary causes. A thorough history is required to screen for these causes. Personally, I use the acronym ‘OCHAPS’ to remember the secondary causes of hypertension:

O: Obstructive sleep apnea. This is one of the most common secondary causes. Patients can be screened for this using the STOP-BANG questionnaire. Diagnosis is confirmed with AHI>=5 on polysomnogram. Treatment includes: 10% weight loss, CPAP, dental appliances, and uvulopalatopharyngoplasty.

C: Cushing’s disease. This results in hypercortisolism. Assess the patient for the following features/signs: abdominal striae, Buffalo hump, hyperglycaemia, moon facies. Investigations include 24-hour urine cortisol. Management varies depending on the underlying cause. 

H: Hyperaldosteronism. Suspect this in patients with hypokalemia. Investigations include aldosterone/renin levels and ratios. Management varies depending on the underlying cause. 

A: Aortic coarctation. Suspect this in younger patients. Assess using upper limb vs. lower limb blood pressure difference. Management is usually surgical.

P: Pheochromocytoma. Suspect in patients presenting with the 5 Ps: pain (headache), palpitations, perspiration, pressure (high), and pallor. Investigations include 24-hour urine total metanephrines. Management is usually surgical.

S: Stenosis of renal arteries. Investigations include abdominal ultrasound. Management is usually surgical.

Resources: 

1. Evaluation of secondary hypertension. Uptodate
2. Overview of hypertension. Uptodate

-IL-

A 'Head to toe' Review of Liver Disease Findings

There are many findings that suggest that a patient has liver disease that are outside of the liver/abdomen itself. Here is a 'head-to-toe' approach to remembering 19 of the findings:

1. Three 'head' signs: temporal wasting, fetor hepaticus, hepatic encephalopathy
2. Seven 'hand' signs: palmar erythema, clubbing, terry’s nails, leukonychia, thenar wasting, asterixis, Duputren’s contracture
3. Four signs of increased estrogen: gynecomastia, testicular atrophy, frontal balding, spider nevi
4. Three peripheral signs: jaundice, easy bruising/petechiae, pitting edema
5. Other: ascites, enlarged liver

*Note: there are many other findings that are suggestive of liver disease that are not included in the above list.

Let us know what your approach to recognizing liver disease findings is!

References: 

1. Cirrhosis and Chronic Liver Failure: Part I. Diagnosis and Evaluation. American Family Physician. https://www.aafp.org/afp/2006/0901/p756.html

-IL-

Necrotizing Fasciitis

During this ambulatory internal medicine selective, I have had the opportunity to assess several patients referred to our clinic for possible cellulitis.Skin and soft tissue infections are common but recognizing the dangerous ones that need prompt admission and treatment from those that can be treated with oral antibiotics as an outpatient is crucial. One of the most notorious soft tissue infections is necrotizing fasciitis, an infection that spreads quickly along fascial layers and can lead to the development of toxic shock syndrome resulting in organ failure and death. There are two clinical types of necrotizing fasciitis, Type I which is a polymicrobial infection with anaerobes (bacteroides, peptostreptococcus) and a facultative anaerobe (enterobacterales or non group A streptococcus) and Type II which is a monomicrobial infection with streptococcus pyogenes (group A strep). 

 

Signs & Symptoms: Signs and symptoms of necrotizing fasciitis typically develop acutely (over the course of hours).

 

Early signs and symptoms:

• Red, warm, swollen area of skin, not well demarcated that spread quickly (mark the area of erythema)
• Severe pain or edema beyond the area of redness
• Fever

Late symptoms:

• Ulcers, blisters, black areas or skin colour changes
• Crepitus of the skin
• Oozing/pus
• Dizziness
• Fatigue
• Nausea
• Diarrhea
• Tachycardia, tachypnea, hypotension

Common Findings on Bloodwork/Imaging:

• WBC: abnormally high or low WBC
• Sodium: may be decreased
• Urea/Creatinine: may be elevated
• CRP: usually elevated
• CK: may be elevated
• Lactate: usually elevated
• Blood and Tissue Cultures: positive (polymicrobial or monomicrobial)
• Arterial Blood Gas: hypoxemia, acidosis
• Radiography: edema extending along fascial planes/soft tissue gas

Management of Necrotizing Fasciitis

The key principles in the management of necrotizing fasciitis are surgical debridement and empiric antibiotics. Delaying surgical debridement by >12 hours has been shown to be associated with an increased need for future debridement, organ failure and higher rates of mortality. Empiric antimicrobial therapy should be started immediately, as well as fluids for hemodynamic support. Recommended empiric regimens include:

• Vancomycin, linezolid, tedizolid or daptomycin and 
• Piperacillin/tazobactam or a carbapenem and
• Clindamycin (for the antitoxin effects)

 

References:

1. Necrotising Fasciitis. BMJ Best Practice. https://bestpractice-bmj-com.myaccess.library.utoronto.ca/topics/en-gb/821/history-exam
2. Necrotizing Soft Tissue Infections. UpToDate. https://www.uptodate.com/contents/necrotizing-soft-tissue-infections?search=necrotizing%20fasciitis&source=search_result&selectedTitle=1~135&usage_type=default&display_rank=1
3. Necrotizing Fasciitis. Centers for Disease Control and Prevention. https://www.cdc.gov/groupastrep/diseases-public/necrotizing-fasciitis.html