This lecture described the diagnostic approach to an adult patient presenting with vague complaints of fatigue, weakness and weight loss

1. Fatigue, Weakness
& Weight Loss
Dr. Zhenya Krapivinsky

2. Learning Objectives
After the completion of this lecture you will be able
to:
1. Be able to generate an initial differential diagnosis
for patients presenting with weakness, fatigue and
weight loss.
2. Have an initial diagnostic approach to investigate
the cause for weakness, fatigue and weight loss.

3. Case 1
• 80 yo woman with no significant past
medical history presents after a single
episode of hematemesis followed by
confusion and depressed mental status.
• In addition, per family, patient ~ 4
months earlier stopped getting out of
bed and has lost 10kg.

4. Case #1
• ROS (obtained from family)
– No fevers
– No night sweats
– Weight loss due to anorexia
– Depressed mood
– Complaining of weakness, fatigue but not joint
pain or paralysis
– No rashes
– No shortness of breath, orthopnea, chest pain,
cough, abdominal pain
– No decrease in urination

5. Case #1
• PMHx
– No history of diabetes
– No history of HTN
– No history of autoimmune disease
– Not taking any medications

6. Failure to Thrive
• Definition failure to thrive
– Person with fatigue, weight loss, decreased
appetite, poor nutrition, inactivity often
accompanied by dehydration, depressive
symptoms, impaired immune function and low
cholesterol.

7. Failure to thrive
• Leads to
– impaired functional status
– morbidity from infection
– pressure ulcers
– ultimately increased mortality
• This syndrome is challenging to address since
it often multiple contributing causes.

8. Serious causes of “failure to thrive”
• 5 categories
– Malignancy
– Endocrine
– Infectious
– Chronic Organ Failure
– Rheumatologic

9. Weight Loss
• Weight loss is the result of decreased energy intake
or increased energy expenditure.
• Progressive involuntary weight loss often indicates a
serious medical illness.
• Clinically important weight loss = more than 5% -
10% of usual body weight over 6 months.

10. Serious Causes of Weight Loss
• Weight Loss with Increased Appetite
– Hyperthyroidism
– Uncontrolled diabetes mellitus
– Malabsorption syndromes

11. Serious Cause of Weight Loss
Weight Loss with Decreased Appetite
1. Malignancy – GI, lung, lymphoma, renal, prostate
2. Endocrine Disease – adrenal insufficiency,
hyperparathyroidism
3. Infectious Disease – TB, HIV, HCV, lung abscess
4. Severe heart, lung, kidney disease
5. Chronic Inflammatory Disease – Sarcoidosis, rheumatoid
6. GI – PUD, cirrhosis, celiac disease, bacterial overgrowth,
chronic pancreatitis

12. Differential Diagnosis
Fatigue/ “Failure to Thrive”
• Malignancy
• Endocrine
• Chronic Infectious
• Chronic Organ Failure
• Rheumatologic
Weight Loss
• Malignancy
• Endocrine
• Chronic Infections
• Severe Heart, Lung, Kidney
Disease
• Chronic Inflammatory
Disease
• GI – PUD, malabsorbtion

13. Malignancy
• Anorexia & weight loss are present in over 50 percent of
cancer patients at the time of diagnosis.
• 25% of patients admitted with involuntary weight loss without
fever will be diagnosed with cancer.
• The most important diagnosis to investigate in the elderly.
• Fatigue & weakness worsened by anemia.
• Most common cancers – Lung, Lymphoma, Stomach CA, Liver
CA, Prostate, Breast, Ovarian, Renal .

14. Endocrine/Metabolic
• Hypothyroidism or hyperthyroidism
• Hypopituitarism
• Hypercalcemia
• Adrenal Insufficiency
• Uncontrolled Diabetes

15. Infectious
• Subacute Bacterial Endocarditis
• Tuberculosis
• Mononucleosis
• Hepatitis
• Parasitic infection
• HIV infection

16. Chronic Organ Failure
• Hippocrates was the first to describe weight loss in
patients with chronic heart failure ( “cardiac cachexia”)
• Chronic obstructive pulmonary disease – cachexia in 30-
70%
• End-Stage Kidney Failure – chronic acidosis
• End-Stage Liver Failure – liver congestion cause nausea,
anorexia, mild encephalopathy

17. Chronic Inflammatory Disease
• Rheumatoid Arthritis
• Sarcoidosis
• Polymyalgia Rheumatica
• Giant Cell Arteritis
• Lupus

18. Less Lethal Causes of Fatigue & Weakness
• 3 categories
– Psychological
– Pharmacological
– Disturbed Sleep

19. Pharmacologic
• Antihypertensive
Medications
• Antipsychotics/anti-
depressants
• Alcohol dependence or
withdrawal
Psychological
• Depression
• PTSD
• Anxiety
• Alcohol/Drug addiction

20. Sleep Disturbance
• Obstructive Sleep Apnea
• Gastroesophageal reflux
• Allergic Rhinitis
• Psychological Causes

21. Suggested Clinical Framework

22. History
1. Severity and temporal pattern of fatigue
a. Onset – abrupt or gradual
b. Course –stable, improving or worsening
c. Impact on daily life – still working, able to take care
of self?
2. Weight loss – anorexia or with normal appetite?
3. Disability – able to do ADL? (Not getting out of bed and
not walking on own is not normal at any age).
4. Fevers & Night Sweats
5. Shortness of breath

23. General Physical Exam
• Vital signs - including weight and height, and orthostatic
blood pressure measurements
• Neck - palpation for lymphadenopathy and thyroid
nodules
• Breast - rule out masses and axillary lymphadenopathy
• Cardiopulmonary - signs of congestive heart failure or
chronic lung disease

24. History: Rule-Out Endocrine Disease
1. Hypothyroidism & Hyperthyroidism
2. Hypoparathyroidism - anorexia, nausea,
constipation, and polyuria
3. Diabetes -polyurea/polydypsia, weight gain or loss
4. Hypopituitary - menstrual periods irregularity
5. Adrenal - nausea/vomiting/anorexia
6. Hypercalcemia – abdominal
pain/constipation/kidney stones

25. History/Physical: Rule out Infectious Disease
• Endocarditis fever, murmur, embolic
stigmata (Roth’s spots)
• Tuberculosis cough, hemoptysis, fever, wt. loss
• Mononucleosis hepatomegally,
lymphadenopathy
• Hepatitis unprotected sex, diarrhea ,
hepatomegally
• Parasitic disease diarrhea
• HIV unprotected sex
• Cytomegalovirus hepatomegally,
lymphadenopathy

26. History: rule out cardiopulmonary disease
• Dyspnea on exertion
• Orthopnea
• PND
• Edema
• Chronic Shortness of breath
• Chronic Cough
• Chest Pain

27. History: rule out rheumatologic disease
• Joint pain swelling
• Fevers
• Weight loss
• Rashes
• History of serositis

28. Focused Lab Investigation
• In a patient without fevers but with vague symptoms of
fatigue, inability to get out of bed and weight los, if a
history does not point to an obvious diagnoses the
following tests should be ordered: in whom no obvious
etiology emerges after a targeted history and physical
initial labs should be:
– FBC
– ESR
– Chemistry: Ionized Calcium, Creatinine, LFTs
– TSH
– HIV, HCV
– Chest x-ray

29. Full Blood Count
• Anemia will be present in about 50% of
patients with cancer.
• Anemia is a strong predictor of TB.
• Approximately 46% of individuals with
rheumatologic disorders will be anemic.

30. Erythrosine Sedimentation Rate
• If High (> 60mm/hr) suspect:
– Polymyalgia Rheumatica
– Chronic Infection (TB, lung abscess)
– Malignancy

31. Anemia + ESR
• Any patient admitted for involuntary weight loss has a
24% probability of having a malignancy.
• Neither ESR or Hemoglobin used separately could
exclude the diagnosis of cancer.
• A low Hemoglobin (Hb) and an elevated ESR has a:
– PPV of 64% for malignancy
– NPB of 91% for malignancy
• Hb < 9 % ESR > 60, probability of cancer 25%  64%
• Hb> 9 & ESR < 20, probability of cancer 25%  9%

32. Hypercalcemia
• Fatigue and weight loss can occur with
hypercalcaemia.
• Hyperparathyroidism & malignancy account for 90%
of cases of hypercalcaemia.
• Hypercalcemia symptoms include: fatigue, weakness,
depression, confusion, GI upsets & polyurea.

33. Renal Impairment
• Chronic renal failure can develop insidiously with non-
specific symptoms such as fatigue, anorexia or
nausea.
• Initial investigations include: serum creatinine and
urinalysis for abnormal sediment and proteinuria.

34. Systemic Autoimmune Diseases
• Fatigue & weigh loss are early feature of some of the
systemic autoimmune diseases such as Systemic Lupus
Erythematous (SLE) and Rheumatoid Arthritis (RA).
• The best initial test for SLE is antinuclear antibodies
(ANA) as it is positive in over 95% of patients with SLE.
• Rheumatoid factor is the first test to screen for RA. It is
positive in 69-90% of patients with RA.

35. Addison’s Disease
• Addison’s disease may be suspected when
patients have a combination of:
–fatigability
–weakness
–mild GI distress
–weight loss
–Anorexia
–Increased pigmentation.
• Screening: 7am cortisol level

36. Thyroid Dysfunction
• TSH testing is appropriate for people who are at an
increased risk of thyroid dysfunction and present
with non-specific symptoms such as tiredness.
• In the majority of situations, TSH should be the sole
initial test of thyroid function.

37. Thyroid Dysfunction
Increased risk of thyroid dysfunction is associated with:
• Increased age
• Autoimmune diseases
• Chronic cardiac failure, pulse >90 or <50 per min,
hypertension
• Menstrual disturbance or unexplained infertility
• The postpartum interval or a previous episode of post
partum thyroiditis
• A history of neck surgery

38. Case #2
• 25 year old woman who recently gave birth to
her second child was seen in an outpatient clinic
for gradual onset of fatigue, anxiety, weight loss,
muscle weakens and a feeling of her "heart
pounding.” She also reported some diffuse joint
pain.
• Family history indicates that her mother has
hyperthyroidism.
• Complete Blood count was done and showed
mild anemia.

39. Case #2
• What physical exam would you do?
• Any additional Labs?

40. Physical Exam
• Vital signs – T 37.9 HR 90 BP 100/60
• Thyroid gland normal, no tremor, eyes normal
• No lymphadenopathy
• Heart/Lungs normal
• No hepatosplenomegally
• No leg edema
• Slight limitation in the range of motion of both
hips, with some decreased muscle strength in
the left leg.

41. Labs
• ESR: 85 mm/hr
• TSH: normal
• HIV Testing: negative
• HCV Antibody: negative
• Hemaglobin: 9mg/dL
• MCV: 85

42. Case # 2
• 6 months later
• Strange red, raised rash on her
cheeks after being out in the
sun.
• Small, raised sores begam to
develop on her legs and arms.
• The joint pain, swelling, and
fatigue continue.
• 7kg weight loss & occasional
chest pain developed

43. Systemic Lupus
• Patient symptoms indicates systemic lupus.
• A butterfly-shaped rash in the malar area of the face is present in
up to 90% of cases.
• Other common symptoms include:’
– Low grade fever
– Fatigue
– Oral ulcers
– Dry eye syndrome
– Discoid rash elsewhere on the body, photosensitivity
– Joint pain (especially in proximal joints of the fingers), pain and swelling in
both hips
– Slight pleural rub.
• The ANA titer is highly sensitive for systemic lupus, with a positive
result in approximately 93% to 100% of individuals with the disease.

44. Case # 3
• A 23-year-old female presented to Emergency with
nausea/vomiting for one week. She also reported 8 months
of progressively worsening fatigue. The patient was
previously very active student, but for the past 8 months she
stopped going to school because of lack of energy. She was
now living with her mother and sleeping most of the day.
• She also reported a poor appetite for 4 months & had lost
7kg.
• She also reported occasional fevers.
• Also reports dry skin and "darkening” of the skin in several
areas of her body.

45. Physical Exam
• Vital signs: BP 93/50 mmHg, HR 104, T 37.9
• There were significant orthostatic changes.
• The patient was a thin, nontoxic appearing & in
no distress.
• She was alert, oriented and cooperative.
• Her examination was otherwise unremarkable,
except for mild skin hyperpigmentation over
the cheeks, knuckles, elbows and knees.
• The thyroid, abdominal, and neurological
examinations were normal.

46. What would you do next?
• Any additional questions on history
you want to ask?
• Any additional physical exam findings
you want to know?
• What labs would you order?

47. Case #3
• Complete Blood Count: normal
• Na+: 111 mmol/L (normal 135-145mmol/L)
• K+: 4.5 mmol/L
• Glucose: 85 mg/dL
• Creatinine: 0.7 mg/dL
• Cortisol (7am): 0.2 ug/dl (normal 10-20 ug/dl )

48. • Given the apparent adrenal insufficiency, in a TB
endemic area and MRI of the abdomen was ordered.
• Magnetic resonance imaging (MRI) showed
asymmetrically enlarged adrenal glands consistent
with adrenal TB.

49. TB Adrenalitis
• TB is the most common cause of adrenal
insufficiency in TB endemic countries.
• Enlargement of both adrenal glands occurs
in 90% of patients.
• Symptoms : weight loss, weakness,
tiredness, orthostatic hypotension, muscle
aches, nausea, vomiting.

50. Case #4
• 60yo man presents with 6 months
of
– fatigue
– 10kg weight loss
– bone pain
– vague diffuse abdominal pain
– polyurea

51. Case #4
• What tests would you order next?

52. Labs
• Hb: 8mg/dL
• ESR: 50mm/hr (normal < 30mm/hr)
• TSH: normal
• Ionized Calcium: 2.5 µmol/L (normal 1-1.4mmol/L)
• Creatinine: 250 µmol/L (normal 53 - 106 µmol/L)
• Glucose: normal
• LFTs: normal
• Chest X-ray: No hilar adenopathy and no infiltrates.

53. Diagnosis
• SPEP: Monoclonal M-spike
• Diagnosis: Multiple Myeloma with hypercalcemia
• Treatment: Patient’s symptoms significantly improved
with aggressive IV hydration and Lasix.
• Symptoms of hypercalcemia - “Stones, bones,
abdominal moans, and psychic groans”.

54. Take Home Points
• Chief complaint: “failure to thrive” is a term used to
describe a constellation of symptoms including: weight
loss, weakness, fatigue, disability
• Differential Diagnosis for “Failure to Thrive”:
– Cancer
– Endocrine Disease – thyroid, parathyroid, adrenal,
diabetes
– Chronic Infection – HIV, TB, abscess, endocarditis
– Chronic Organ Failure
– Rheumatologic/Chronic Inflammatory Disease –
Lupus, RA, Sarcoidosis

55. Take Home Points
Initial Diagnostic Tests:
1. Complete Blood Count
2. ESR
3. TSH
4. Calcium
5. Creatinine
6. LFTs
7. Chest X-ray

56. • 80 yo woman with no significant past medical
history, presents after a single episode of
hematemesis, followed by confusion and
depressed mental status.
• In addition, per family, the patient had stopped
getting out of bed for the past 4 months. She
also had lost 10kg.
Back to Case #1

57. Back to Case #1
• Review of systems (obtained from family)
– No fevers
– No night sweats
– 10kg Weight loss due to anorexia
– Depressed mood
– Complaining of weakness &fatigue, but not joint
pain or paralysis.
– No rashes
– No shortness of breath, orthopnea, chest pain,
cough or abdominal pain.
– No decrease in urination

58. Physical Exam
• Frail, old woman with altered mental status.
• + Asterixis
• Mild icterus and conjunctival pallor
• No JVD, normal heart exam
• Normal lung exam
• Abdomen without ascites or
hepatosplenomegally
• Extremities without edema or joint swelling

59. • Hb 6.0
• MCV 75
• ESR: 90
• HIV-
• Anti-HCV antibody is +
• Creatinine, LFTs, Calcium normal
Back to Case #1

60. • Initial Impression: the patient was suspected to have
Hepatitis C related liver cirrhosis associated with a
variceal bleed. The variceal bleed was then complicated by
hepatic encephalopathy.
• Abdominal US: cirrhotic liver with multiple hypoechoic
mass.
• Alfa Fetal Protein (AFP): 1015ng/ml (normal <6.0 ng/mL)
Back to Case #1

61. Back to Case #1
• Diagnosis:
– Liver cirrhosis complicated by hepatocellular
carcinoma.
• Treatment:
– Patient’s mental status, appetite and overall
quality of life improved significantly after
initiating lactulose and treating her underlying
mild chronic encephalopathy.