This document provides information on evaluating patients presenting with fatigue, weakness, and weight loss. It reviews common differential diagnoses and recommended initial laboratory tests. Four clinical cases are presented and discussed. The first case involves an 80-year-old woman who presented with hematemesis, confusion, and a 10kg weight loss over 4 months. Her initial workup revealed anemia and elevated ESR, suggesting a serious underlying condition needs to be investigated.

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
panceatitis

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, murmure, embolic
stigmata
• Tuberculosis cough, hymoptysis, fever, wt.loss
• Mononucleosis hepatomegally,
lymphadenopath
• 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 presenting with vague
symptoms of : fatigue, inability to get out of bed,
weight loss 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 xray

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 (> 60) suspect:
– polymyalgia rheumatica
– chronic infection (TB, lung abscess)
– malignancy

31. Anemia + ESR
• Any patient admitted to our wards for involuntary
weight loss has a 24% probability of having a
malignancy.
• Neither ESR or Hb used separately could exclude the
diagnosis of cancer.
• Hemoglobin + 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, probablity of cancer 25%  9%

32. Hypercalcemia
• Fatigue and weightloss can occur with
hypercalcaemia.
• Hyperparathyroidism & malignancy account for 90%
of cases of hypercalcaemia.
• Hypercalcemia symptoms: 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 Erythematosus
(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 – positive
in 69-90% of patients

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 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 seen in OPD for gradual
onset of fatigue, anxiety, weight loss, muscle
weakens and a feeling of her "heart
pounding.” Also some diffuse joint pain.
• Family history indicates that her mother has
hyperthyroidism.
• FBC done 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
• TSH – normal
• HIV negative
• HCV negative
• Hb – 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 begin to
develop on her legs and
arms.
• The joint pain, swelling, and
fatigue continue.
• 7kg weight loss & occasional
chest pain.

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 the Emergency
complaining of 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 months & had lost 7kg.
• She also reported occasional fevers
• Also reports dry skin and "darkening” of the skin in several
areas

45. Physical Exam
• Vital signs 93/50 mmHg HR 104 beats/min T
37.9
• There were significant orthostastic 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
• FBC: normal
• Na+ 111 mmol/L (normal range 135-
145)
• K+ 4.5 mmol/L
• Glucose 85 mg/dL
• Creatinine 0.7 mg/dL
• 7am cortisol level – 0.2 micrograms/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 Rwanda.
• 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: 50
• TSH: normal
• Ionized Calcium: 2.5 mmol/L (normal
1-1.4mmol/L)
• Creatinine: 250 micromol/L
• Glucose: normal
• LFTs: normal
• Chest X-ray: no hilar adenopathy, no
infiltrate

53. Diagnosis
• SPEP: monoclonal M-spike
• Diagnosis: multiple myeloma with
hypercalcemia
• Treatment: patients 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”, weight
loss, weakness, fatigue, disability
• Differential Diagnosis
– Cancer
– Endocrine Disease – thyroid, parathyroid, adrenal,
diabetes
– Chronic Infection – HIV, TB, abcess, endocarditis
– Chronic Organ Failure
– Rheumatologic/Chronic Inflammatory Disease –
lupus, RA, sarcoidosis

55. Take Home Points
Screening Labs
1. FBS
2. ESR
3. TSH
4. Calcium
5. Creatinine
6. LFTs
7. Chest X-ray

56. 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.

57. 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

58. Physical Exam
• Frail, old woman with altered mental
status.
• + Asterixis
• Mild icterus and pallor
• No JVD, normal heart exam
• Normal Lung Exam
• Abdomen: no ascites, no
hepatosplenomegally
• Ext: no edema, no joint swelling

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

60. Case #1
• Patient was suspected of having HCV liver
cirrhosis associated with varices bleed,
complicated by hepatic encephalopathy.
• Abdominal US: cirrhotic liver with multiple
hypoechoic mass
• Alfa fetal protein: 1015

61. Case #1
• Diagnosis: Liver cirrhosis complicated by
Hepatocellular Carcinoma
• Treatment: Patients mental status,
appetite and overall quality of life
improved significantly after initiating
lactulose and treating her underlying
mild chronic encephalopathy.

62. Thank you kindly
Questions?