Rhabdomyolysis

Rhabdomyolysis is a pathological syndrome caused by skeletal muscle cell
damage due to increased intracellular Ca2+ levels.

*Causes are classified as:*

1. Hereditary- Most frequent is McArdle's disease which is the deficiency
of muscle phosphorylase, an enzyme essential for glycogenolysis.
2. Acquired- Divided into a) Traumatic- Crush Syndrome, Accidents, Intense
exercise
b) Non Traumatic- Alcohol abuse, Drugs
(hypolipidemic agents, amphetamines, antipsychotics,
diuretics(loops),seizures, coma
The above causes contribute to increase in intracellular Ca2+ levels in
two ways: 1) direct muscle injury 2)rupture of sacrolemma

*Pathophysiological mechanisms involving rhabdomyolysis:*

1) decrease in ATP production- Increase in intracellular Ca2+ causes
mitochondrial dysfuntion which decreases ATP production and causes
peroxidation of DNA, lipids and proteins. This peroxidation causes
increase in ROS (reactive oxygen species) leading to mitochondrial and DNA
mutations --> coding sequence change in repiratory chain protein-->
dysfunction of ETS (electron transport chain) --> decrease in ATP
production.

2) apoptosis- Caused by increased mitochindrial Ca2+ and increased
intracellular Ca2+. The apoptosis causes activation of proteases and
phospholipases A2 which causes rupture of sacrolemma. The membrane rupture
inturn increases Ca2+ levels.

*Clinical Presentation:*

There is a wide spectrum of presentation of rhabdomyolysis. The classic
triad includes: muscle pain, muscle weakness and reddish brown urine. 50%
of the cases involve central muscle groups like thigh and shoulders. The
reddish brown urine is a powerful diagnostic element. If severe, malaise,
fever, tachycardia, nausea and vomiting might be seen.

*Lab findings:*
* *
*Biochemical findings- *

Increased- myoglobin, CPK-MM, K+, phos, uric acid, myosin heavy chain, LDH,
aldolase, creatinine, urea:creatinine, fibrinogen degradation products, PT
Decreased- Platelets, intravascular volume, Albumin, pH
Ca2+ levels first decrease and then increase

*UA-* dipstick: Heme positive, pH - (acidic)
Color: reddish- brown
Microscopic analysis- 0 or few RBCs (less than 5 per high power
field)
urine radioimmunoassay- Myoglobinuria
Usine sediment- Myoglobin casts, epithelial casts.
* *
*Variations of Myoglobin and CPK during the course of Rhabdomyolysis:*

Myoglobin- It is the first enzyme to increase but returns to normal within
24 hours due to rapid clearance. The half life is 2-3 hours. It increases
in 1-3 hours, peaks in 8-12 hours, making it the pathognomonic for
diagnosis of rhabdomyolysis. Nomal serum myoglobin levels are <100
micrograms/L and urine <10micrograms/L.
CPK- It increases after myoglobin and peaks in 24 hours and detectable for
3 days and returns to normal in 3-5 days after cessation of injury. It
elevates in first 12 hours after onset of injury and the half life is 1.5
days. This makes the the test more useful for diagnosis and assessment of
severity of muscular injury due to delayed clearance.
* *
*Myoglobinuria *

Myoglobinuria is detected with urine dipstick microscopically and
macroscopically as reddish brown urine ( if severe, levels can be

300microgram/L). Urine dipstick detects myoglobin >0.3 mg/L. It does not

disticnguich between Hgb, myoglobin or Hgb rich RBcs. Acidic urine in rhabdomyolysis facilitates precipitation of myoglobin cylinders (Tamm
Horsfall ptoteins) and Uric acid crystals, which is the main mechanism of
Acute renal failure in Rhabdomyolysis. The final diagnosis of myoglobinuria
and myoglobinemia is done with immunologic and radioimmunologic methods
which detect antibodies against Myoglobin.

*CPK*

Types of CPK
1) CPK-MM- skeletal muscles
2) CPK-MB- myocardium
3) CPK-BB- Brain and Kidneys
If CPK does not increase more than 5000U/L in the first 3 days, the risk
of developing ARF is low because for rhabdomyolysis to cause ARF, CPK
levels should be more than 15,000 U/L.

*Other tests:*
The most life threatening electrolyte imbalance is increased K+ which along
with increased Ca2+ can cause fatal ventricular arrhythmias.
Carbonic anhydrase III has higher specificity for diagnosis of muscular
injury than serum myoglobin and CPK, but it is an expensive and difficult
test. Another specific one is heavy chain myosin fragments but is not
widely available. LDH, SGOT and aldolase increase during the course of
rhabdomyolysis but lack in specificity. Decrease in Albumin is a poor
prognostic sign because it is a proof of capillary damage and albumin
extravasation. Increased anion gap( normal = 12+/- 2) is noticed due to
overproduction of phosphoric and organic phosphate. Normal Urea/Creatinine
ratio of 10:1 changes to 5:1 in early stages but eventually returns to
normal or above normal ratio due to increase in urea levels because of
protein catabolism in skeletal muscle.

Strong diagnostic elements include combination of central/diffuse myalgia
and presence of darkly colored urine or heme positive urine dipstick and
increase in CPK levels, increase serum and urine myoglobin.


Sources:George D. Giannoglou, Yiannis S. Chatzizisis, Gesthimani Misirli.
The syndrome of rhabdomyolysis:Pathophysiology and diagnosis: European
Journal of Internal Medicine, Volume 18, Issue 2, pp 90-100, 2007

submitted by:

Prabhpreet Dhaliwal
Medical Student 4