Differentials

Common

Stomach cancer

History

Helicobacter pylori infection, prior gastric ulcer or atrophic gastritis, epigastric/abdominal pain, nausea, hematemesis, melena, dysphagia

Exam

epigastric tenderness or mass, lymphadenopathy, hepatomegaly, signs of anemia, abrupt onset of multiple seborrheic keratoses (rare)

1st investigation
  • upper GI endoscopy with biopsy:

    tumor visualized

  • stool heme test:

    positive for occult blood

Other investigations
  • CBC:

    anemia

  • serum iron:

    decreased

  • CT abdomen/pelvis:

    metastatic lesions

    More

Colorectal cancer

History

rectal bleeding, abdominal pain, change in stool caliber; more likely to be advanced if presenting with unintentional weight loss

Exam

abdominal distention or tenderness, abdominal or rectal mass

1st investigation
  • colonoscopy:

    tumor visualized

  • stool heme or quantitative fecal immunochemical test:

    positive for occult blood

    More
Other investigations
  • CBC:

    anemia

  • serum iron:

    decreased

  • CT abdomen/pelvis:

    metastatic lesions

    More

Esophageal cancer

History

smoking, alcohol use (squamous cell carcinoma), Barrett esophagus, progressive dysphagia, painful swallowing, fatigue, pain, nausea

Exam

may be normal

1st investigation
  • esophagogastroduodenoscopy (EGD) with biopsy:

    mucosal lesion, histology (squamous cell carcinoma or adenocarcinoma)

Other investigations
  • CBC:

    may show microcytic anemia

Pancreatic cancer

History

unintentional weight loss very common, nausea, anorexia, abdominal bloating, upper abdominal pain/discomfort

Exam

abdominal tenderness/mass, jaundice

1st investigation
  • abdominal ultrasound:

    pancreatic mass, biliary dilation

    More
  • LFTs:

    abnormal

Other investigations
  • pancreatic protocol CT:

    pancreatic mass, extent of spread

    More
  • endoscopic ultrasound:

    small tumors in pancreas

    More

Hepatoma

History

cirrhosis, hepatitis B or C infection, right upper quadrant pain

Exam

right upper quadrant mass, abdominal tenderness, jaundice, hepatomegaly, ascites

1st investigation
  • abdominal ultrasound:

    intrahepatic mass

  • CT abdomen/pelvis:

    intrahepatic mass

  • LFTs:

    abnormal

Other investigations

    Small cell lung cancer

    History

    cough, hemoptysis, dyspnea, chest pain; bone pain, headache, seizures (metastases); altered mental status, abdominal pain, muscle weakness (paraneoplastic syndromes)

    Exam

    lung exam may be normal or show abnormalities (e.g., wheeze, rales, egophony, dullness to percussion); confusion, personality changes (metastases)

    1st investigation
    • CT chest:

      pulmonary mass, mediastinal lymphadenopathy, pleural effusion, consolidation

      More
    • chest x-ray:

      pulmonary mass, mediastinal lymphadenopathy, pleural effusion, consolidation

    Other investigations
    • MRI/CT brain:

      brain metastases

    • serum electrolytes:

      may show hypercalcemia, hyponatremia

    Non-small cell lung cancer

    History

    cough, hemoptysis, dyspnea, chest pain; bone pain, headache, seizures (metastases)

    Exam

    lung exam may be normal or show abnormalities (e.g., wheeze, rales, egophony, dullness to percussion); confusion, personality changes (metastases)

    1st investigation
    • CT chest:

      pulmonary mass, mediastinal lymphadenopathy, pleural effusion, consolidation

      More
    • chest x-ray:

      pulmonary mass, mediastinal lymphadenopathy, pleural effusion, consolidation

    Other investigations
    • MRI/CT brain:

      brain metastases

    • serum electrolytes:

      may show hypercalcemia, hyponatremia

    Non-Hodgkin lymphoma

    History

    night sweats, fatigue/malaise, enlarged lymph nodes

    Exam

    fever, lymphadenopathy, splenomegaly, hepatomegaly

    1st investigation
    • CBC:

      leukocytosis, leukopenia, anemia, thrombocytopenia (variable)

    • LDH:

      elevated

    Other investigations
    • CT chest and abdomen/pelvis:

      may show enlarged lymph nodes and other sites of disease

      More
    • bone marrow biopsy:

      positive

      More
    • flow cytometry:

      clonal population of lymphoma cells identified

      More

    Hodgkin lymphoma

    History

    usually young adults but has second peak in sixth decade, night sweats, chest pain (if mediastinal mass present), generalized pruritus

    Exam

    fever, lymphadenopathy (rubbery, firm, nontender), splenomegaly, hepatomegaly

    1st investigation
    • CBC:

      leukocytosis, anemia, thrombocytopenia, eosinophilia (variable)

    • LDH:

      elevated

    Other investigations
    • serum electrolytes:

      possible hypercalcemia

    • CT chest and abdomen/pelvis:

      may show enlarged lymph nodes and other sites of disease

      More
    • excisional lymph node biopsy:

      Hodgkin cells

      More

    Chronic leukemia

    History

    unintentional weight loss more common compared with acute leukemia, night sweats

    Exam

    fever, lymphadenopathy

    1st investigation
    • CBC:

      anemia, neutropenia, thrombocytopenia

      More
    • peripheral blood smear:

      increased lymphocytes

    • flow cytometry:

      clonal population of lymphocytes

    Other investigations
    • bone marrow biopsy:

      may show marrow infiltration by leukemic cells (CLL); granulocytic hyperplasia (CML)

    Multiple myeloma

    History

    fatigue, bone pain, infections

    Exam

    pallor, pathologic fractures

    1st investigation
    • CBC:

      anemia

    • serum electrolytes:

      possible hypercalcemia

    • serum creatinine:

      elevated

    • serum/urine electrophoresis:

      monoclonal M protein band present

      More
    Other investigations
    • bone marrow biopsy:

      >10% myeloma plasma cells

    • x-ray bone series:

      may see lytic lesions

    Oropharyngeal cancer

    History

    smoking/chewing tobacco, alcohol use, oral pain, sore throat, dysphagia

    Exam

    neck mass, cervical swelling or lymphadenopathy, tumor may be seen with laryngoscopy

    1st investigation
    • CT head and neck:

      tumor visualized

      More
    • biopsy of lesion:

      positive

      More
    Other investigations

      Laryngeal cancer

      History

      smoking/chewing tobacco, alcohol use, dysphagia, painful swallowing, sore throat, hoarseness

      Exam

      neck mass, cervical swelling or lymphadenopathy, supraglottic/glottic mass may be seen with laryngoscopy

      1st investigation
      • CT head and neck:

        tumor visualized

        More
      Other investigations
      • rigid direct laryngoscopy:

        ulcerative, friable, necrotic mass involving the larynx

        More

      Ovarian cancer

      History

      pelvic pain/pressure, abdominal bloating, increased abdominal girth (bulky disease or ascites), constipation, nausea, gastrointestinal or vaginal bleeding (less common); weight loss more common in advanced disease or metastases

      Exam

      adnexal mass, ascites

      1st investigation
      • pelvic ultrasound:

        adnexal mass

        More
      Other investigations
      • CA-125 level:

        increased

        More

      Prostate cancer

      History

      obstructive urinary symptoms, bone pain, pelvic pain; weight loss more common in advanced disease or metastases

      Exam

      enlarged prostate with nodule or asymmetry, bone tenderness

      1st investigation
      • prostate specific antigen (PSA) level:

        elevated

        More
      Other investigations
      • MRI:

        suspicious focus in prostate; dynamic contrast-enhanced imaging suspicious for malignancy

      • prostate biopsy:

        abnormal or cancer cells; cancer cells are graded and the two most common patterns added to give a Gleason score ranging from 6 to 10

        More

      Breast cancer

      History

      breast lump, bone pain; weight loss more common in advanced disease or metastases

      Exam

      palpable breast mass, lymphadenopathy, bone tenderness

      1st investigation
      • mammogram:

        breast mass

        More
      • breast ultrasound:

        breast mass

      Other investigations
      • MRI:

        heterogeneously enhancing area and significant architectural distortion

        More

      Celiac disease

      History

      diarrhea, bloating, abdominal pain/discomfort, fatigue

      Exam

      pallor, dermatitis herpetiformis

      1st investigation
      • total IgA:

        may be normal or deficient

        More
      • IgA-tTG (tissue transglutaminase):

        elevated

        More
      • esophagogastroduodenoscopy:

        atrophy and scalloping of mucosal folds; nodularity and mosaic pattern of mucosa

      • small bowel (duodenal) biopsy:

        presence of intraepithelial lymphocytes, villous atrophy, and crypt hyperplasia

        More
      Other investigations
      • endomysial antibody (EMA):

        elevated

        More
      • IgG-based antibodies:

        elevated

        More
      • HLA typing:

        positive HLA-DQ2/DQ8

        More
      • CBC:

        low Hb and microcytic red cells

      • skin biopsy:

        granular deposits of IgA at the dermal papillae of lesional and perilesional skin by direct immunofluorescence

      Exocrine pancreatic insufficiency

      History

      previous pancreatitis, cystic fibrosis, diarrhea, oily/floating/foul-smelling stools; unintentional weight loss usually only occurs in severe cases

      Exam

      abdominal tenderness (chronic pancreatitis)

      1st investigation
      • fecal fat:

        high

      Other investigations
      • vitamin A, D, E, K levels:

        may show low levels

        More

      Crohn disease

      History

      can occur in younger patients (ages 15-40 years) and peaks again in sixth decade, abdominal pain, diarrhea (may be bloody), bloating, fatigue

      Exam

      abdominal tenderness, perianal lesions, blood in stool

      1st investigation
      • CBC:

        anemia

        More
      • stool heme test:

        positive for occult blood

      • endoscopy:

        typical lesions seen (e.g., aphthous ulcers, edema, cobblestoning, skip lesions)

        More
      • tissue biopsy:

        mucosal bowel biopsies demonstrate transmural involvement with noncaseating granulomas

      Other investigations

        Ulcerative colitis

        History

        can occur in younger patients (ages 20-40 years) and peaks again in sixth decade, abdominal pain, diarrhea (usually bloody), rectal bleeding, fatigue, arthritis

        Exam

        abdominal tenderness, blood in stool

        1st investigation
        • CBC:

          anemia

          More
        • stool heme test:

          positive for occult blood

        • colonoscopy:

          rectal involvement, continuous uniform involvement, loss of vascular marking, diffuse erythema, mucosal granularity, normal terminal ileum

        • tissue biopsy:

          continuous distal disease, mucin depletion, basal plasmacytosis, diffuse mucosal atrophy, absence of granulomata, anal sparing

        Other investigations

          Mesenteric ischemia

          History

          cardiovascular risk factors, postprandial pain (mild-to-severe), nausea/vomiting, diarrhea, hematochezia/melena; weight loss may be severe

          Exam

          abdominal tenderness, abdominal bruits may be present; exam may be normal

          1st investigation
          • CT scan with contrast/CT angiogram:

            bowel wall thickening, bowel dilation, pneumatosis intestinalis, portal venous gas, occlusion of the mesenteric vasculature, bowel wall thickening with thumbprinting sign suggestive of submucosal edema or hemorrhage

            More
          • doppler ultrasound (vascular/duplex):

            flow abnormalities and stenoses in celiac/superior mesenteric arteries

            More
          Other investigations
          • mesenteric angiography:

            high-grade stenoses in celiac/superior mesenteric arteries

            More

          Depression

          History

          comorbid medical/psychiatric conditions (may coexist with other conditions in differential for unintentional weight loss), anhedonia, depressed mood, functional impairment, appetite changes, sleep disturbance, libido changes, low energy, poor concentration, excessive guilt, suicidal ideation; weight change (loss or gain) can be variable

          Exam

          psychomotor slowing

          1st investigation
          • clinical diagnosis:

            diagnosis is made based on history and exam; should meet Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, Text Revision (DSM-5-TR) criteria

            More
          Other investigations

            Bipolar disorder

            History

            episodes of mania (elevated mood, increased energy, perceived decreased need for sleep, impulsivity) with periods of depression; weight loss may be significant

            Exam

            grandiosity, pressured speech, irritability, psychosis, depression (depending on whether manic or depressive episode)

            1st investigation
            • clinical diagnosis:

              diagnosis is made based on history and exam; should meet Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, Text Revision (DSM-5-TR) criteria

            Other investigations

              Generalized anxiety disorder

              History

              excessive worry for at least 6 months, anxiety, muscle tension, functional impairment, irritability, restlessness, poor concentration, fatigue, sleep disturbance; weight loss is not part of diagnostic criteria

              Exam

              usually normal

              1st investigation
              • clinical diagnosis:

                diagnosis is made based on history and exam; should meet Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, Text Revision (DSM-5-TR) criteria

                More
              Other investigations

                Anorexia nervosa

                History

                comorbid psychiatric disorders, fear of gaining weight, food restriction, distorted body image, amenorrhea, suicidal ideation, bingeing/purging, history may be denied by patient

                Exam

                low BMI, bradycardia, hypothermia, hypotension, hair loss, muscle wasting, dental erosion (if coexisting bulimia), signs of cardiomyopathy; should meet Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, Text Revision (DSM-5-TR) criteria

                1st investigation
                • CBC:

                  may have anemia, mild leukopenia, or thrombocytopenia

                • basic metabolic panel:

                  may be deranged

                • serum glucose level:

                  hypoglycemia

                • serum creatinine level:

                  variable

                  More
                • TFTs:

                  low T3, normal T4, normal TSH

                  More
                • LFTs:

                  may be abnormal

                Other investigations
                • bone densitometry:

                  helps illustrate effects of severe weight loss to patients who deny or minimize presence of eating disorder symptoms

                  More

                Substance misuse

                History

                substance use/misuse (e.g., opioids, cocaine, amphetamine, cannabis, inhalant, hallucinogen, benzodiazepine, alcohol), comorbid psychiatric disorders, inadequate nutrition; weight loss when use/misuse is severe

                Exam

                depends on substance

                1st investigation
                • clinical diagnosis:

                  diagnosis is made based on history and exam and depends on substance

                Other investigations

                  Parkinson disease

                  History

                  bradykinesia, cognitive impairment, dementia

                  Exam

                  rigidity, resting tremor, shuffling gait, cogwheeling

                  1st investigation
                  • clinical diagnosis:

                    diagnosis is made based on history and exam

                    More
                  Other investigations
                  • dopaminergic agent trial:

                    improvement in symptoms

                    More

                  Dementia

                  History

                  progressive cognitive dysfunction, memory loss, taste changes; weight loss generally associated with advanced disease

                  Exam

                  cognitive impairment, delirium, depression

                  1st investigation
                  • cognitive testing:

                    cognitive impairment

                    More
                  Other investigations
                  • MRI brain:

                    Infarcts and/or white matter disease

                    More

                  Hyperthyroidism

                  History

                  palpitations, tremor, fatigue, weakness (may be subtle), heat intolerance, hair thinning/loss, anxiousness; older patients have fewer classic symptoms

                  Exam

                  tachycardia, fine tremor, hyperreflexia, bilateral lid retraction, proptosis

                  1st investigation
                  • serum TSH level:

                    suppressed (primary)

                    More
                  Other investigations

                    Tuberculosis

                    History

                    exposure to infection, endemic location, immunosuppression, fever, cough, night sweats, malaise, hemoptysis, dyspnea; weight loss is more common with reactivation

                    Exam

                    pulmonary: tachypnea, decreased breath sounds, crackles, dullness to percussion; extrapulmonary: findings dependent upon site, lymphadenopathy common

                    1st investigation
                    • chest x-ray:

                      may demonstrate atelectasis from airway compression, pleural effusion, consolidation, pulmonary infiltrates, mediastinal or hilar lymphadenopathy, upper zone fibrosis

                      More
                    • sputum acid-fast bacilli smear and culture:

                      presence of acid-fast bacilli (Ziehl-Neelsen stain) in specimen

                      More
                    • acid-fast bacilli smear and culture of extrapulmonary biopsy specimen:

                      positive

                      More
                    • nucleic acid amplification tests (NAAT):

                      positive for M tuberculosis

                      More
                    Other investigations
                    • bronchoscopy and bronchoalveolar lavage:

                      positive for acid-fast bacilli

                      More
                    • lateral flow urine lipoarabinomannan (LF-LAM) assay:

                      positive

                      More
                    • contrast-enhanced chest computed tomography scan:

                      primary TB: mediastinal tuberculous lymphadenitis with central node attenuation and peripheral enhancement, delineated cavities; postprimary TB: centrilobular nodules and tree-in-bud pattern

                      More

                    Adverse medication effects

                    History

                    started new medication; common drugs include anticonvulsants (e.g., topiramate, zonisamide), antidepressants (e.g., selective serotonin-reuptake inhibitors, bupropion), stimulants (e.g., dextroamphetamine), diabetes medications (e.g., metformin; exenatide, glucagon-like peptide-1 receptor agonists, sodium-glucose co-transporter 2 inhibitors), antibiotics and other medications that cause diarrhea, cholinesterase inhibitors (e.g., donepezil), diuretics, laxatives, thyroid hormone (from misuse); withdrawal of drugs that support/maintain weight loss (e.g., pancreatic enzymes, mirtazapine); no other significant history

                    Exam

                    usually normal

                    1st investigation
                    • medication withdrawal trial:

                      reversal of weight loss

                      More
                    Other investigations

                      Sarcopenia

                      History

                      difficulty rising from chair and climbing stairs, difficulty performing activities of daily living, presence of comorbidities affecting muscle mass and/or function

                      Exam

                      low hand grip strength, slow gait, emaciation

                      1st investigation
                      • dual-energy x-ray absorptiometry (DXA):

                        reduced appendicular skeletal muscle and skeletal mass index

                        More
                      • CT:

                        low muscle mass and muscle quality (intramuscular fat infiltration)

                        More
                      • MRI:

                        low muscle mass and muscle quality (intramuscular fat infiltration)

                        More
                      Other investigations
                      • bioimpedance analysis (BIA):

                        reduced

                        More

                      Uncommon

                      Cholangiocarcinoma

                      History

                      primary sclerosing cholangitis, fever, right upper quadrant pain, pruritus; usually presents late

                      Exam

                      right upper quadrant mass, abdominal tenderness, jaundice, hepatomegaly

                      1st investigation
                      • LFTs:

                        abnormal; typically greater elevation in bilirubin and alkaline phosphatase than aminotransferases

                      • abdominal ultrasound:

                        biliary duct dilation, bile duct tumor

                        More
                      Other investigations
                      • serum CA 19-9 level:

                        elevated

                        More
                      • serum CEA level:

                        elevated

                        More

                      Acute leukemia

                      History

                      unintentional weight loss less common compared with chronic leukemia/lymphoma, fatigue, infections, bone pain, bleeding

                      Exam

                      fever, pallor, hypotension, petechiae, bone tenderness, ecchymosis

                      1st investigation
                      • CBC:

                        anemia, leukopenia, thrombocytopenia

                      • peripheral blood smear:

                        presence of blasts; Auer rods (acute myeloid leukemia)

                      Other investigations
                      • LDH:

                        elevated

                      • bone marrow biopsy:

                        presence of >20% blasts; Auer rods (acute myeloid leukemia)

                      Zollinger-Ellison syndrome

                      History

                      GERD, peptic ulcer disease, diarrhea, abdominal pain, fatigue, weight loss uncommon; may be part of multiple endocrine neoplasia syndrome (type 1) or associated with hyperparathyroidism or pituitary tumors

                      Exam

                      abdominal tenderness, pallor

                      1st investigation
                      • fasting serum gastrin level:

                        elevated

                        More
                      Other investigations

                        VIPoma

                        History

                        young-to-middle age, profuse watery diarrhea (nonbloody), nausea, fatigue

                        Exam

                        flushing, poor skin turgor, muscle weakness, muscle cramps

                        1st investigation
                        • VIP radioimmunoassay:

                          elevated

                          More
                        Other investigations

                          Carcinoid syndrome

                          History

                          diarrhea, wheezing, GI bleeding, weight loss due to diarrhea is uncommon

                          Exam

                          flushing, tumor is not usually palpable

                          1st investigation
                          • 24-hour urinary 5-hydroxyindoleacetic acid:

                            elevated

                          Other investigations

                            Peptic ulcer disease

                            History

                            nonsteroidal anti-inflammatory drug (NSAID) use, Helicobacter pylori infection, epigastric pain (especially after meals, classically with a delay of a few hours), dark stools (if bleeding)

                            Exam

                            epigastric tenderness

                            1st investigation
                            • H pylori breath test or stool antigen test:

                              positive if H pylori present

                            • stool heme test:

                              positive for occult blood

                            • upper GI endoscopy:

                              peptic ulcer visualized

                            Other investigations
                            • fasting serum gastrin level:

                              elevated levels in pernicious anemia and other hypochlorhydric states results in low specificity

                            Chronic hepatitis

                            History

                            risk of exposure (hepatitis B or C), fatigue, malaise, right upper quadrant pain, pruritus

                            Exam

                            fever; jaundice, edema, ascites (cirrhosis); exam may be normal

                            1st investigation
                            • LFTs:

                              abnormal

                            • serology:

                              hepatitis B antigen: positive; hepatitis C antibody: positive

                            Other investigations
                            • HBV or HCV PCR:

                              positive

                            • serum bilirubin level:

                              may be elevated in advanced disease

                            Esophageal webs, rings, and diverticula

                            History

                            usually asymptomatic; dysphagia, decreased oral intake (severe cases)

                            Exam

                            usually normal

                            1st investigation
                            • endoscopy:

                              esophageal pathology visualized

                            Other investigations
                            • esophagram:

                              esophageal pathology visualized

                              More

                            Small intestinal bacterial overgrowth (SIBO)

                            History

                            prior gastrointestinal surgery/short bowel syndrome, systemic sclerosis (scleroderma), diarrhea, abdominal pain, bloating; unintentional weight loss in severe cases

                            Exam

                            usually normal

                            1st investigation
                            • hydrogen breath test:

                              increased hydrogen after administration of sugar/carbohydrate

                              More
                            Other investigations
                            • CBC:

                              may have anemia, variable

                            Gastroparesis

                            History

                            diabetes mellitus, postprandial epigastric pain or nausea/vomiting; unintentional weight loss in severe cases

                            Exam

                            usually normal

                            1st investigation
                            • gastric emptying scintigraphy:

                              delayed transit time through stomach

                            Other investigations
                            • upper gastrointestinal endoscopy:

                              Retained food in the stomach

                              More

                            Postsurgical complications

                            History

                            prior gastrointestinal surgery/short bowel syndrome, diarrhea, abdominal pain, nausea

                            Exam

                            surgical scars, abdominal tenderness

                            1st investigation
                            • clinical diagnosis:

                              diagnosis is made based on history and exam

                            Other investigations

                              Stomatitis

                              History

                              malnutrition, dentures, prior radiation therapy or chemotherapy, oral trauma, oral pain, xerostomia

                              Exam

                              erythema or ulceration of oral mucosa

                              1st investigation
                              • clinical diagnosis:

                                diagnosis is made based on history and exam

                              Other investigations
                              • CBC:

                                variable; may show leukocytosis and/or neutropenia

                              Bulimia nervosa

                              History

                              recurrent episodes of binge eating and compensatory behavior (e.g., purging, fasting, exercise), depression, low self-esteem, concern about body image/weight, menstrual irregularities

                              Exam

                              dental erosion, Russell sign (scarring over dorsum of hands from inducing vomiting), arrhythmia, parotid hypertrophy; should meet Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, Text Revision (DSM-5-TR) criteria

                              1st investigation
                              • CBC:

                                may have anemia

                              • basic metabolic panel:

                                may be deranged

                              • LFTs:

                                may be abnormal

                              Other investigations
                              • serum electrolytes:

                                may show hypokalemia or alkalosis

                              Multiple sclerosis

                              History

                              focal neurologic deficits lasting >24 hours in different regions, vision loss, numbness, pain, weakness, dizziness, fatigue, depression

                              Exam

                              internuclear ophthalmoplegia, limb weakness, sensory deficits

                              1st investigation
                              • MRI brain:

                                white matter plaques

                                More
                              • MRI spinal cord:

                                demyelinating lesions

                                More
                              Other investigations
                              • CSF evaluation:

                                increased oligoclonal bands

                                More

                              Amyotrophic lateral sclerosis

                              History

                              progressive upper and lower motor neuron deficits, limb weakness, dementia (uncommon), dyspnea

                              Exam

                              muscle atrophy, fasciculations, weakness (lower motor neuron involvement); muscle atrophy, weakness, hyperreflexia (upper motor neuron involvement); facial or oropharyngeal weakness (bulbar involvement); decreased air movement, crackles from atelectasis (respiratory involvement)

                              1st investigation
                              • electromyography:

                                evidence of diffuse, ongoing, chronic denervation

                              Other investigations
                              • repetitive nerve stimulation:

                                modest decreases in compound motor action amplitude after repetitive stimuli

                              Prion disease

                              History

                              Creutzfeld-Jakob disease, prion exposure, rapidly progressive cognitive dysfunction, sleep disturbance, personality changes, dementia

                              Exam

                              myoclonus, altered mental status, ataxia

                              1st investigation
                              • MRI brain:

                                often demonstrates hyperintensity in the cerebral cortex (cortical ribboning), basal ganglia (caudate and putamen), and thalamus on diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) sequences, and hypointensity (restricted diffusion) on attenuated diffusion coefficient map (ADC) sequences

                                More
                              Other investigations
                              • EEG:

                                generalized slowing, focal or diffuse, and periodic polyspike-wave complexes and sharp waves

                                More
                              • brain biopsy:

                                vacuolation (spongiform changes), neuronal loss, astrogliosis, presence of pathogenic prion (PrPSc) by immunohistochemistry or western blot, may show amyloid

                              Cardiac cachexia syndrome

                              History

                              symptoms of advanced heart failure (e.g., dyspnea on exertion, fatigue, orthopnea and paroxysmal nocturnal dyspnea, peripheral edema)

                              Exam

                              muscle wasting/atrophy, signs of advanced heart failure (e.g., S3 gallop, rales, lower extremity edema, elevated jugular venous pressure, neck vein distention); distinguish intentional weight loss (i.e., diuretic therapy) from unintentional (i.e., cardiac cachexia)

                              1st investigation
                              • clinical diagnosis:

                                diagnosis is made based on history and exam; patient has a prior diagnosis of heart failure

                                More
                              Other investigations

                                Poststroke complications

                                History

                                prior stroke, depression, cognitive impairment, dysphagia, arm/hand weakness

                                Exam

                                decreased oropharyngeal function, speech and/or swallowing impairment

                                1st investigation
                                • swallow study:

                                  inability to swallow properly

                                  More
                                Other investigations

                                  Pulmonary cachexia syndrome

                                  History

                                  symptoms of advanced COPD or interstitial lung disease (e.g., cough, dyspnea)

                                  Exam

                                  muscle wasting/atrophy, signs of advanced COPD or interstitial lung disease (e.g., decreased breath sounds and air movement, increased work of breathing, lung crackles, wheezing, hypoxia, tachypnea)

                                  1st investigation
                                  • clinical diagnosis:

                                    diagnosis is made based on history and exam; patient has a prior diagnosis of COPD or lung disease

                                    More
                                  Other investigations

                                    Cystic fibrosis

                                    History

                                    cough, dyspnea, diarrhea, oily/floating stool, failure to gain weight (children), chronic pulmonary/sinus infections

                                    Exam

                                    lung hyperinflation, rales (if infection), wheezing

                                    1st investigation
                                    • sweat test:

                                      positive

                                    Other investigations
                                    • genetic testing:

                                      positive

                                    Microscopic polyangiitis

                                    History

                                    overlap with granulomatosis with polyangiitis and lung disease, hematuria

                                    Exam

                                    fever, joint tenderness or synovitis

                                    1st investigation
                                    • urinalysis:

                                      presence or red blood cells, casts

                                    • antineutrophil cytoplasmic antibody (ANCA):

                                      positive

                                      More
                                    • antimyeloperoxidase antibody:

                                      positive

                                    Other investigations
                                    • conventional angiography or magnetic resonance angiography:

                                      beading, aneurysm, or smooth, tapering vessel stenosis

                                    Renal cachexia syndrome

                                    History

                                    symptoms of advanced renal failure (e.g., fatigue, edema)

                                    Exam

                                    muscle wasting/atrophy, symptoms of uremia (e.g., confusion, bleeding, pericardial rub)

                                    1st investigation
                                    • clinical diagnosis:

                                      diagnosis is made based on history and exam; patient has a prior diagnosis of renal failure

                                      More
                                    Other investigations
                                    • kidney biopsy:

                                      variable depending on etiology

                                    Diabetes mellitus

                                    History

                                    polyuria, polydipsia, infections, history of poor glycemic control may be chronic symptoms of type 1; nausea, vomiting, anorexia (diabetic ketoacidosis); type 1 more frequently presents with or is complicated by weight loss than type 2, and ketosis compounds weight loss

                                    Exam

                                    acetone breath, Kussmaul respiration, abdominal tenderness (diabetic ketoacidosis); dry mucous membranes, hypotension, tachycardia, tachypnea, decreased level of consciousness (diabetic ketoacidosis or hyperosmolar hyperglycemic state)

                                    1st investigation
                                    • HbA1c:

                                      6.5% or greater

                                    • plasma glucose:

                                      elevated

                                    Other investigations
                                    • serum creatinine level:

                                      elevated (diabetic ketoacidosis)

                                    • serum sodium level:

                                      hyponatremia (diabetic ketoacidosis)

                                    • serum potassium level:

                                      hyperkalemia (diabetic ketoacidosis)

                                    • ABG:

                                      acidosis (diabetic ketoacidosis)

                                    Adrenal insufficiency

                                    History

                                    metastases, tuberculosis, autoimmune endocrinopathies (primary adrenal insufficiency); glucocorticoid exposure (tertiary adrenal insufficiency); fatigue, decreased appetite, weakness, diarrhea, abdominal pain

                                    Exam

                                    orthostasis, hyperpigmentation (primary adrenal insufficiency), shock (adrenal crisis)

                                    1st investigation
                                    • morning serum cortisol:

                                      <3 micrograms/dL

                                      More
                                    • high-dose ACTH stimulation test:

                                      serum cortisol <18 micrograms/dL

                                      More
                                    Other investigations
                                    • serum sodium level:

                                      hyponatremia

                                    • serum potassium level:

                                      possible hyperkalemia

                                    Hypopituitarism

                                    History

                                    infiltrative disease (e.g., sarcoidosis, hemochromatosis), hypotension, fatigue; headache, vision loss (pituitary adenoma)

                                    Exam

                                    coarse voice, thickened skin, bradycardia, delayed deep tendon reflexes (hypothyroidism); decreased muscle mass, testicular atrophy (hypogonadism); increased fat mass, decreased muscle mass (growth hormone deficiency); no hyperpigmentation; loss of body hair, growth retardation

                                    1st investigation
                                    • TFTs:

                                      low TSH and T4

                                    • insulin-like growth factor (IGF-1) level:

                                      low

                                    • 8 a.m. cortisol and ACTH:

                                      low

                                    • testosterone, FSH, LH (men):

                                      low

                                    • estradiol, FSH, LH (women):

                                      low

                                    Other investigations

                                      Pheochromocytoma

                                      History

                                      may be part of multiple endocrine neoplasia syndrome (type 2); symptoms can be episodic; headache, sweats, palpitations, tremor, weakness

                                      Exam

                                      tachycardia, diaphoresis, hypertension, orthostasis

                                      1st investigation
                                      • serum catecholamines:

                                        elevated

                                        More
                                      Other investigations
                                      • 24-hour urine collection for catecholamines and metanephrines:

                                        elevated

                                        More

                                      Rheumatoid arthritis

                                      History

                                      symmetric polyarthritis, joint pain/swelling

                                      Exam

                                      joint subluxation/destruction (advanced disease)

                                      1st investigation
                                      • rheumatoid factor:

                                        positive

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                                      • anticyclic citrullinated peptide antibody:

                                        positive

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                                      • x-ray affected joints:

                                        erosive arthritis, osteopenia

                                        More
                                      Other investigations
                                      • CBC:

                                        mild anemia

                                      • ESR and CRP:

                                        elevated

                                        More

                                      Systemic lupus erythematosus

                                      History

                                      rash, fatigue, arthralgia/arthritis, Raynaud phenomenon, chest pain, dyspnea

                                      Exam

                                      fever, malar rash, joint tenderness, hematuria, pleural effusion, pericardial rub, confusion (lupus cerebritis), thrombosis

                                      1st investigation
                                      • antinuclear antibody (ANA), anti-dsDNA:

                                        positive

                                        More
                                      • CBC:

                                        anemia, leukopenia, thrombocytopenia

                                      • serum creatinine level:

                                        elevated

                                      • urinalysis:

                                        hematuria, proteinuria

                                      • ESR and CRP:

                                        may be elevated

                                      Other investigations
                                      • antiphospholipid antibody:

                                        may be positive

                                      Granulomatosis with polyangiitis

                                      History

                                      cough, dyspnea, hemoptysis, sinusitis, earache, fatigue, arthralgia/arthritis, myalgia, numbness, muscle weakness, abdominal pain, diarrhea, nausea/vomiting; presentation variable depending on systems affected

                                      Exam

                                      fever, hematuria, skin lesions (e.g., purpura), joint tenderness/swelling, may have signs of consolidation (single lung nodules may have otherwise normal lung exam)

                                      1st investigation
                                      • chest x-ray:

                                        lung mass, infiltrates, pleural effusion, lymphadenopathy

                                      • CT chest:

                                        lung mass, infiltrates, pleural effusion, lymphadenopathy

                                      • antineutrophil cytoplasmic antibody (ANCA):

                                        positive

                                      Other investigations
                                      • tissue biopsy:

                                        granulomatous inflammation, necrosis, and vasculitis

                                        More

                                      Polyarteritis nodosa

                                      History

                                      history of hepatitis B or C, myalgia/arthralgia, paresthesia, abdominal pain, purpura, livedo reticularis, skin ulcers, muscle tenderness

                                      Exam

                                      fever, weight loss, neurologic manifestations (e.g., mononeuritis multiplex and peripheral neuropathy), cutaneous manifestations (e.g., nodules and livedo reticularis), renal manifestations (e.g., hypertension), gastrointestinal manifestations (e.g., abdominal pain), high diastolic BP, mononeuritis multiplex

                                      1st investigation
                                      • CBC:

                                        anemia, elevated platelets, and WBC count

                                      • ESR and CRP:

                                        elevated

                                      • complement:

                                        reduced

                                      • antineutrophil cytoplasmic antibody (ANCA):

                                        negative

                                      • antinuclear antibody (ANA), anti-dsDNA:

                                        negative

                                      • rheumatoid factor:

                                        negative

                                      • anticyclic citrullinated peptide antibody:

                                        negative

                                      Other investigations
                                      • angiography:

                                        saccular or fusiform aneurysms and stenotic lesions in the mesenteric, hepatic, and renal arteries and their subsequent branches

                                      Systemic sclerosis (scleroderma)

                                      History

                                      positive family history, hand swelling, Raynaud phenomenon, skin thickening/tightness, loss of hand function, dysphagia, heartburn, abdominal bloating, melena, myalgia/arthralgia, fatigue

                                      Exam

                                      digital pits/ulcers, sclerodactyly, joint tenderness, telangiectasias, crackles

                                      1st investigation
                                      • antinuclear antibody (ANA):

                                        positive

                                      • CBC:

                                        may be normal or show anemia

                                      • ESR and CRP:

                                        may be elevated

                                      Other investigations

                                        Sarcoidosis

                                        History

                                        cough, dyspnea, fatigue, arthralgia, photophobia, vision changes; symptoms are highly variable and depend on organ involved

                                        Exam

                                        wheezing, rhonchi, lymphadenopathy

                                        1st investigation
                                        • chest x-ray:

                                          hilar and/or paratracheal adenopathy with upper lobe predominant, bilateral infiltrates; pleural effusion (rare)

                                        • CBC:

                                          may show anemia or leukopenia

                                        • LFTs:

                                          abnormal

                                        • serum creatinine:

                                          may be elevated

                                        • serum calcium:

                                          hypercalcemia

                                        • PFTs:

                                          restrictive or obstructive pattern (or mixed)

                                        Other investigations

                                          Mixed connective tissue disease (overlap syndromes)

                                          History

                                          digital pallor/pain, Raynaud phenomenon, arthralgia/arthritis, myalgia, swollen hands, dyspnea, cough, heartburn

                                          Exam

                                          sclerodactyly, nail fold vascular changes, lymphadenopathy, hematuria

                                          1st investigation
                                          • CBC:

                                            may show anemia or leukopenia

                                          • ESR and CRP:

                                            elevated

                                          • rheumatoid factor:

                                            may be positive

                                          • antinuclear antibody (ANA):

                                            positive

                                          • anticyclic citrullinated peptide antibody:

                                            may be positive

                                          • antiribonucleoprotein antibodies:

                                            positive

                                          Other investigations
                                          • urinalysis:

                                            variable; may show proteinuria, hematuria, occasional RBC casts

                                          Adult-onset Still disease

                                          History

                                          daily-spiking fevers, rash, abdominal pain, nausea, arthralgia/arthritis

                                          Exam

                                          salmon-colored rash (especially during febrile periods), lymphadenopathy, joint tenderness/swelling

                                          1st investigation
                                          • serum ferritin level:

                                            may be very high

                                            More
                                          • CBC:

                                            anemia, leukocytosis

                                          • ESR and CRP:

                                            elevated

                                          Other investigations

                                            HIV infection

                                            History

                                            injection drug use, unprotected sex, needle stick injury, transfusions of blood or blood products prior to 1986 or in regions without adequate testing, night sweats, diarrhea, oral ulcers, altered mental status, opportunistic infections; weight loss more common with advanced disease

                                            Exam

                                            fever, skin rashes, oral thrush, muscle wasting (advanced disease), Kaposi sarcoma

                                            1st investigation
                                            • serum HIV ELISA:

                                              positive

                                              More
                                            • serum p24 antigen:

                                              positive

                                            • serum HIV DNA PCR:

                                              positive

                                              More
                                            Other investigations

                                              Mycobacterium avium complex (MAC)

                                              History

                                              underlying lung disease, cough, dyspnea, fatigue

                                              Exam

                                              fever, lymphadenopathy, rales, or consolidation

                                              1st investigation
                                              • blood culture:

                                                positive for MAC

                                              • sputum culture:

                                                positive for MAC

                                              • lymph node biopsy:

                                                positive for MAC

                                                More
                                              Other investigations

                                                Histoplasmosis

                                                History

                                                exposure to spores, endemic region, immunosuppression, cough, dyspnea, headache, abdominal pain, chest pain; weight loss more common with disseminated disease

                                                Exam

                                                fever, scattered crackles, bronchial breathing, distant breath sounds

                                                1st investigation
                                                • chest x-ray/CT:

                                                  may be normal or show focal infiltrates, hilar and mediastinal lymphadenopathy, calcified granulomas, pulmonary nodules, diffuse interstitial or reticulonodular infiltrates, cavitary lesions, or pleural effusion

                                                • sputum culture:

                                                  positive for Histoplasma capsulatum

                                                • antigen testing:

                                                  positive for H capsulatum antigen

                                                Other investigations
                                                • immunodiffusion precipitin test:

                                                  positive for H capsulatum antibody

                                                Amebiasis

                                                History

                                                exposure history (e.g., visit to endemic area), immunosuppression, diarrhea, dysentery, abdominal pain

                                                Exam

                                                fever, abdominal tenderness

                                                1st investigation
                                                • stool antigen detection:

                                                  positive for parasite antigen

                                                • PCR of stool:

                                                  amplification of amebic DNA

                                                • serum antibody test:

                                                  positive for antiamebic antibodies

                                                Other investigations
                                                • stool microscopy:

                                                  identification of Entamoeba in stool

                                                  More

                                                Giardiasis

                                                History

                                                exposure history (contaminated water), nonbloody diarrhea (severity varies), malaise, bloating; weight loss in severe and/or chronic disease

                                                Exam

                                                may have abdominal tenderness

                                                1st investigation
                                                • stool antigen detection:

                                                  positive for cyst wall

                                                  More
                                                Other investigations

                                                  Cryptosporidiosis

                                                  History

                                                  exposure history (contaminated water), diarrhea, abdominal pain, loss of appetite; may be mild and self-limiting unless patient is immunosuppressed

                                                  Exam

                                                  may have abdominal tenderness

                                                  1st investigation
                                                  • stool microscopy:

                                                    positive for Cryptosporidium cysts

                                                    More
                                                  Other investigations

                                                    Cystoisosporiasis

                                                    History

                                                    exposure history to Cystoisospora belli (contaminated food or water), nonbloody diarrhea; may be mild and self-limiting unless patient is immunosuppressed

                                                    Exam

                                                    may have abdominal tenderness

                                                    1st investigation
                                                    • stool microscopy:

                                                      positive for Cystoisospora belli oocysts

                                                      More
                                                    Other investigations

                                                      Cyclosporiasis

                                                      History

                                                      exposure history to Cyclospora (contaminated food or water), nonbloody diarrhea; may be mild and self-limiting unless patient is immunosuppressed

                                                      Exam

                                                      may have abdominal tenderness

                                                      1st investigation
                                                      • stool microscopy:

                                                        positive for Cyclospora cysts

                                                        More
                                                      Other investigations

                                                        Strongyloidiasis

                                                        History

                                                        history of exposure (e.g., contaminated soil), abdominal pain, change in bowel habit; pulmonary syndrome (e.g., cough, wheezing) may develop; weight loss can occur in immunosuppressed patients

                                                        Exam

                                                        may be normal

                                                        1st investigation
                                                        • stool microscopy:

                                                          positive for strongyloides larvae

                                                        • CBC:

                                                          eosinophilia

                                                        • serology:

                                                          positive

                                                          More
                                                        Other investigations

                                                          Infective endocarditis

                                                          History

                                                          prior dental work, injection drug use, prosthetic heart valves, cough, hemoptysis, dyspnea, night sweats, fatigue, myalgia/arthralgia, weakness

                                                          Exam

                                                          fever, cardiac murmur, Osler nodes, Janeway lesions

                                                          1st investigation
                                                          • blood culture:

                                                            bacteremia, fungemia

                                                            More
                                                          • echocardiogram:

                                                            valvular vegetation

                                                          Other investigations

                                                            Whipple disease

                                                            History

                                                            male gender, diarrhea, abdominal pain, joint pain

                                                            Exam

                                                            fever, may be normal

                                                            1st investigation
                                                            • endoscopy with biopsy:

                                                              villous blunting with periodic acid-Schiff (PAS) staining in macrophages

                                                              More
                                                            Other investigations

                                                              Bartonella infection

                                                              History

                                                              Bartonella henselae often follows bite or scratch from a cat (other types are associated with travel or indigent/homeless people), abdominal pain, nausea/vomiting

                                                              Exam

                                                              fever, papular/pustular lesion

                                                              1st investigation
                                                              • serology (Bartonella henselae):

                                                                positive

                                                              • culture:

                                                                positive for B henselae

                                                              • lymph node biopsy:

                                                                granuloma formation, microabscesses, follicular hyperplasia

                                                              Other investigations

                                                                Inadequate nutrition

                                                                History

                                                                older age, poverty, inadequate resources, taste changes, dental problems, fewer social interactions, reduced or no access to food and different types of food

                                                                Exam

                                                                signs of starvation

                                                                1st investigation
                                                                • clinical diagnosis:

                                                                  diagnosis is made based on history and exam

                                                                Other investigations

                                                                  Elder abuse/neglect

                                                                  History

                                                                  recurrent injuries, unstable home environment, inconsistent/changing history, unexplained/inconsistent injuries

                                                                  Exam

                                                                  signs of starvation, ecchymosis, burn marks, bone fractures, head injuries

                                                                  1st investigation
                                                                  • x-ray/CT area of injury:

                                                                    may show bone fracture or intracranial bleeding

                                                                  Other investigations
                                                                  • clinical photograph:

                                                                    record of bruises or wounds

                                                                  Child abuse/neglect

                                                                  History

                                                                  recurrent injuries, unstable home environment, inconsistent/changing history, unexplained/inconsistent injuries

                                                                  Exam

                                                                  signs of starvation, ecchymosis, burn marks, bone fractures, head injuries

                                                                  1st investigation
                                                                  • x-ray/CT area of injury:

                                                                    may show bone fracture or intracranial bleeding

                                                                  Other investigations
                                                                  • clotting profile/coagulation studies:

                                                                    normal, mild abnormalities may be present in head trauma

                                                                    More

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