Patient 20: Muscle pain and fatigue during fasting

1) Definizione del paziente e della storia

sesso: male of Turkish origin
età: 19
Peso: **
Statura: **
BMI: **

Anamnesi patologica remota

He lives in Germany since three month. Here he works with his parents in a fruit and vegetable trades company.
As his family he respects Islamic rules and observer strictly the ramadan: fasting starts early in the morning and it ends at sunset.

The patient told his doctor that the hard work and fasting make his legs and his arms always weaker.

He referred cramping in his heels and progressing into his thighs and lower trunk, producing severe muscle pain.

During hard work , his legs would become increasingly painful so he would have to stop.

An NSAID taken did not relieved the pain.

The patient was first seen by his family doctor about age 10 for leg pains that appeared few hours after physical exercise : prolonged, even though relatively mild muscle activity, like short running in cross-country, would give him muscle fatigue and later muscle pain.

At the time the doctor called them "growing pains" but these continued into his teen years.

Anamnesi patologica prossima

Now, physical examination showed his legs were swollen and severe weakness was apparent when he tried to move the affected muscles.

The doctor suggests that undergo him some diagnostic test :

The findings included

blood tests
serum creatinine 475 µml/L (normal: less than 110 µml/L).

serum creatinine kinase: 359 U/L (normal:55-215 U/L).

triglycerides: high

%{color: green}lactate level%33.33 mg/dL (3.7 mmol/L)(normal:1.80-18.01 mg/dL or 0.2-2.0 mmol/L)

urine analysis
urine dipstick positive for hemoproteins (hemoglobin and/or myoglobin).

urine myoglobin: positive

2) Le basi molecolari degli eventi descritti, tenendo conto di tutti i sintomi ed utilizzando i link alle informazioni pertinenti

Before any imaging studies, the urinalysis can provide a great deal of information. Many urine specimens are first tested by dipstick.The dipstick urinalysis records a reaction between hydrogen peroxide and chromagen that is catalyzed by hemoglobin. This reaction results in a green color change of the chromagen that is visible on the dipstick.

Multistix (Blood)

Neg

Trace

(1+)

(2+)

(3+)

(4+)

Hemoprotein results:

• 1+: Equivalent to1+ hemoglobin in 5–10 RBCs/μL
• 2+: Equivalent to hemoglobin in 25 RBCs/μL
• 3+: Equivalent to hemoglobin in 50 RBCs/μL
• 4+: Equivalent to hemoglobin in ≥250 RBCs/μL

Heme is found within hemoglobin (free in the urine or within erythrocytes) or myoglobin. Thus, the reaction is very sensitive and will detect hematuria,
hemoglobinuria and myoglobinuria as indicated in the table below.

 

Hematuria	Hemoglobinuria	Myoglobinuria
Mechanism - RBCs lyse on contact with the reagent pad, causing a positive reaction (speckled pattern may result if low-grade)	Mechanism - free Hb filtered into urine as a result of hemoglobinemia (usually detectable as a visibly red plasma).	Mechanism - free Mb filtered into urine as a result of myoglobinemia (not visually detectable in plasma).
Clinical - Bleeding into urinary space (can occur at any level of the urinary or reproductive tract). Commonly due to inflammation, trauma, neoplasia, hemostatic disorders.	Clinical - Intravascular hemolysis of any cause (immune-mediated, toxic, mechanical, infectious, etc).	Clinical - Myocyte injury allowing release of myoglobin which reaches bloodstream and is readily filtered at the glomeruli.

 

• Hematuria: is the presence of red blood cells (erythrocytes) in the urine. It can be a sign that there is a kidney stone or a tumor in the ureter, urinary bladder, prostate, or urethra, kidneys and the urinary tract, ranging from trivial to lethal. If white blood cells are found in addition to red blood cells, then it is a signal of urinary tract infection.
  
• Hemoglobinuria: is a condition in which the oxygen transport protein hemoglobin is found in abnormally high concentrations in the urine.The condition is often associated with hemolytic anemia, in which red blood cells are destroyed, thereby increasing levels of free plasma hemoglobin. The excess hemoglobin is filtered by the kidneys, which release it into the urine, giving urine a red colour.
• Myoglobinuria : is the presence of myoglobin in the urine. This reflecting muscle injury and is usually associated with rhabdomyolysis or muscle destruction.
  
  
  
  

  Rhabdomyolysis is etiologically heterogeneous, most cases being apparently the result of acquired causes, such as mechanical or vascular damage.
  Recurrent rhabdomyolysis preceded by exercise or infection is more likely to have an underlying metabolic defect,and strategic diagnostic procedures are warranted.
  
  History and physical examination are likely to identify the acquired and drug-related forms.
  
  However, one has to bear in mind that sometimes myoglobinuria with episodes of dark urine is ignored, and pronounced muscle pain after only light exercise is not considered as a sign of disease.
  
  Screening for metabolic disorders (carnitine profile, amino acids, tandem mass spectrometry) may point in specific directions.
  
  Muscle biopsy for histologic and biochemical analysis should be performed.
  
  However, in a significant proportion of individuals, no cause of rhabdomyolysis can be identified.
  

  Acquired causes of rhabdomyolysis

  Excessive use of muscle force (e.g., sports, seizures, dystonia)
  Muscle damage (e.g., crush, cold, ischemia, embolism)
  
  Infections (bacterial/viral/fungal)
  
  Temperature changes
  
  Inflammatory myopathies (polymyositis, vasculitis)

  
  Drug-related cases of rhabdomyolysis

  • Induction of an autoimmune reaction (e.g., cyclosporine, penicillamine)
  • Hypokalemia (amphotericin, caffeine)
  • Membrane disruption (cimetidin, colchicine)
  • Disturbance of Na/K ATPase (antidepressants, arsen, azathioprin, bezafibrates)
  • Neuroleptic syndrome (all neuroleptics, lithium)
  • Serotonergic syndrome (amphetamines, MAO-inhibitor, SSRI)
  • Statins

  Metabolic-toxic causes of rhabdomyolysis

  Defects of glucose/glycogen metabolism (e.g., McArdle disease, Tarui disease).
  Deficiencies of the six enzymes involved in glycogen breakdown (phosphorylase, phosphorylase kinase, phosphofructokinase, phosphoglycerate kinase, phosphyglycerate mutase, lactate dehydrogenase) result in exercise intolerance and recurrent rhabdomyolysis.
  
  

  Defects of lipid metabolism (carnitine deficiency).
  Mitochondrial β-oxidation of long-chain fatty acids is a major source of energy production, particularly at times of stress or fasting.
  
  Skeletal muscle can use carbohydrates or lipids as fuel, depending on the degree of activity.
  At rest or during prolonged low-intensity exercise, about 70% of the energy requirement is met by the oxidation of long-chain fatty acids.
  Two defects of lipid metabolism primarily affecting the skeletal muscle are known: carnitine palmitoyltransferase II deficiency and primary carnitine deficiency characterized by progressive proximal weakness and cardiomyopathy.
  

  Defects of oxidative phosphorylation (complex II deficiency, complex III defect, cytochrome c oxidase deficiency)
  

  Malignant hyperthermia

  Dystrophinopathies (Duchenne muscular dystrophy,Becker muscular dystrophy)